case study of alcohol poisoning

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• v.5(4); 2020

Forensic appraisal of death due to acute alcohol poisoning: three case reports and a literature review

a Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China

b Institute of Criminal Scientific Technology, Shanghai Public Security Bureau, Pudong Branch, Shanghai, China

c Forensic Laboratory, Criminal Science and Technology Institute, Shanghai Public Security Bureau, Shanghai, China

Death due to acute alcohol poisoning lacks specific anatomical characteristics, compared with other deaths due to drug poisoning. We report three forensic cases of death from acute alcohol poisoning due to inhibition of the respiratory centre and eventual asphyxia. Blood alcohol concentrations in the three fatalities were 5.28, 3.33 and 3.78 mg/mL, respectively. Lethal doses and blood alcohol concentrations showed differences between individuals. Detailed auxiliary tests besides autopsy were undertaken. These cases show that forensic scientists should exclude other causes of death, combine the autopsy with auxiliary tests, and then make an appraisal.

Introduction

Alcohol is the psychoactive substance encountered most often in forensic toxicology [ 1 ]. Moderate consumption of alcohol can reduce the risk of cardiovascular diseases and type 2 diabetes mellitus [ 2 ], contribute to formation of positive and optimistic lifestyles, and improve quality of life [ 3 ]. However, alcohol abuse can trigger alcohol-related diseases, a trend of consuming alcohol at a younger age, and can lead to violent behaviour [ 4–7 ]. At high blood alcohol concentrations (BACs; >4 mg/mL) people are likely to harm themselves or suffer blunt trauma through accidental falls [ 8 ].

Alcohol abuse can also cause death. According to World Health Organization reports, ∼3.3 million people worldwide die due to alcohol consumption each year, which accounted for 5.9% of all deaths in 2012 [ 9 ]. Excessive consumption of alcohol can cause death by drowning, traffic accidents or violence. A study in Slovakia showed that death due to acute alcohol poisoning (AAP) accounts for a significant proportion of all deaths related to alcohol consumption [ 10 ]. Similar results have been found in women [ 11 ]. Death due to AAP is a serious consequence of heavy drinking. Alcohol can inhibit the central nervous system (CNS), cause respiratory depression and, eventually, lead to death by asphyxia [ 12 , 13 ]. Autopsies of cases of death due to AAP lack specific anatomical–pathological findings, compared with other subjects within forensic medicine. Forensic scientists must, therefore, exclude other suspicious causes of death and combine auxiliary tests to reach the correct conclusion.

In forensic medicine, prior alcohol consumption and the quantity of alcohol intake are important for determination of responsibility of criminal and civil cases. It is important to judge death by AAP correctly. We assessed three fatal cases of AAP and, combined with a literature review, conducted a retrospective analysis and appraisal of AAP cases leading to death.

Case presentation

A 44-year-old male was found deceased at home at 10 pm. After collection, his body was stored frozen. We conducted an autopsy 10 days after his death. External examination showed that his face, lips and nails were marked by cyanosis. A small rupture (0.3 cm × 0.3 cm) was found on his right occipitalis muscle. Internal examination revealed a thickened intima and lipid deposition in the left anterior descending coronary artery (LADCA), type-I stenosis of the LADCA lumen, cardiac and pulmonary interstitial congestion, severe pneumo-oedema and light haemorrhage of the gastric mucosa ( Figure 1 ). The pathological diagnosis was: (1) severe pneumo-oedema, (2) cardiac and pulmonary congestion, and (3) small rupture of the right occipitalis muscle (0.3 cm × 0.3 cm).

Light haemorrhage of the gastric mucosa (arrow).

Central blood (without a fluoride preservative) and gastric contents were taken for toxicology testing, and samples were stored at 4 °C before testing. The BAC was estimated by headspace gas chromatography using a method described previously [ 14 ]. A total of 0.10 mL of blood was diluted with tert-butanol (40.0 µg/mL; 0.50 mL as the internal standard). The same method was employed for the two cases described below. Toxicology testing showed that the BAC was 5.28 mg/mL. Common toxins, including hypnotic sedative drugs, insecticides and tetramine, were not detected in the submitted samples of blood or gastric contents. After investigation, we found that this man had consumed a whole bottle (500 mL) of spirit (ethanol content: 52%) at noon on the same day that he died. Thus, we concluded that this man’s cause of death was consistent with AAP.

The deceased was a 27-year-old female. She drank ∼450 mL of Hennessy cognac (ethanol content: 40%) with some people over the span of one night, and then went with other people to a restaurant, where she drank ∼150 mL of spirit (ethanol content: 35%). Subsequently, the woman slipped into a coma and was sent to a hospital. The attending physicians gave her an intravenous drip, but the woman died. The clinical diagnosis noted that the woman had drunk alcohol before slipping into a coma, her breathing and heartbeat had stopped, and her carotid pulse had disappeared by the time the ambulance arrived. After collection, her body was stored frozen.

We conducted an autopsy 17 days after her death. External examination showed that the face, lips and nails of both hands were marked by cyanosis ( Figure 2 ). There was an injection-needle mark on the dorsum of her left hand which was set during medical treatment. Internal examination revealed pale-red oedematous fluid in some alveolar spaces. The pathological diagnosis was pneumo-oedema due to alcohol consumption. Central blood (without a fluoride preservative) was taken for toxicology and stored at 4 °C before tests. Toxicology revealed the BAC to be 3.33 mg/mL. Blood tests (monoclonal antibody board test) for morphine, pethidine, cocaine, marijuana, ketamine, methadone, amphetamine and methamphetamine were negative. Thus, we concluded that the woman’s cause of death was consistent with AAP.

Lips (A) and nails of both hands (B) were marked by cyanosis.

A 19-year-old male who had been healthy was found in an abnormal state at ∼10 pm after drinking two paper cups of spirit (ethanol content: 36%) and a paper cup of beer (ethanol content: 8%) at a party. The capacity of each paper cup was ∼250 mL. Without too much delay, he was sent to a hospital, but efforts to revive him proved futile. After collection, his body was stored frozen.

We conducted an autopsy 18 days after his death. External examination showed his lips and nails to be marked with cyanosis. There was an injection needle mark on the dorsum of his left hand (due to insertion of an intravenous drip at the hospital). Internal examination revealed some meaningful signs. The cut surface of the lungs showed congestion, and there were some small haemorrhagic spots on the lung bases ( Figure 3 ). Most of the alveolar space was filled with pale-red oedematous fluid. The schistose regions of alveolar spaces were filled with red blood cells. Blood capillaries of alveolar walls were ectatic and congestive, and pulmonary interstitial congestion was present. A few haemorrhagic spots were observed on the schistose regions of the fundus gastric mucosa. A high level of congestion was found in the blood vessels of the gastric mucosa. Subarachnoid and cerebral parenchymal vascular congestion were also documented. The pathological diagnosis was: (1) pulmonary congestion, pneumo-oedema and localized pneumorrhagia, (2) focal haemorrhage of the gastric mucosa, and (3) cerebral haemorrhage and encephaloedema. Central blood (without a fluoride preservative), urine and gastric contents were taken for toxicology testing, and all samples were stored at 4 °C before testing. Toxicology testing revealed the BAC to be 3.78 mg/mL. Urinary tests for opioids, amphetamines and ketamine were negative. Hypnotic sedative drugs, insecticides or tetramine were not detected in his blood, urine or gastric contents. After investigation, we found that this man drank alcohol heavily at the party and had not slept well for 2 days previously. Thus, we concluded that the cause of this man’s death was consistent with AAP.

Small haemorrhagic spots on lung bases (arrow).

Discussion and conclusion

The relationship between CNS depression and alcohol intoxication has been demonstrated [ 13 ]. Hence, people who appear to die from AAP often have asphyxia-related features. The three cases reported in the present study exhibited some important signs of asphyxia, such as cyanosis of the lips and nails, pneumo-oedema, pulmonary congestion and alveolar spaces being filled with pale-red oedematous fluid under microscopic examination. In Case 1, there was some haemorrhage in the gastric mucosa. In Case 3, we found some haemorrhagic spots on the schistose regions of the fundus gastric mucosa. These features were caused by acute injury to the gastric mucosa due to excessive consumption of alcohol. Alcohol can stimulate the gastric mucosal epithelium and submucosal vessels directly, and can change hormone levels in the gastrointestinal tract by mediating inflammation and thereby aggravating gastric mucosal injury [ 15 , 16 ].

The autopsy results of AAP-related death are not specific, so we should exclude other causes of death, such as sudden death, mechanical injury, mechanical asphyxia or electrocution. Alcohol intake is a risk factor for sudden cardiac death [ 17 ]. In Case 1, we found a thickened intima, lipid deposition in the LADCA and type-I stenosis in the LADCA lumen, but the latter was too light (Grade I: lumen area decreased by 1%–25%) to interrupt the cardiac blood supply, let alone cause cardiac arrest. We did not find pathological changes leading to sudden cardiac death either, so we ruled out this possibility. In addition, although a rupture (0.3 cm × 0.3 cm) was found on the right occipitalis muscle, its range was limited, and we did not detect a skull fracture or obvious intracranial haemorrhage. Therefore, we could exclude death by craniocerebral injury. Alcohol intoxication can result in vomiting, food regurgitation and paralysis of the pharyngeal reflex, which make it easier to die from asphyxia via aspiration of gastric contents [ 18 ]. According to the anatomy of asphyxia-related death caused by aspiration, vomit in the trachea, bronchi and bronchioles may be found. In the three cases reported here, there was no blockage in the trachea, bronchi or bronchioles due to foreign bodies.

In addition to autopsy, we used auxiliary tests, including a BAC test and other routine toxicology tests, to determine the cause of death. Through case investigations, it has been established that AAP-related death is often associated with a history of heavy drinking. Compared with chronic alcoholism, AAP shows a higher BAC but the acetone concentration is not increased remarkably. These findings may be related to alcohol-related damage to organs and tissues, chronic tolerance to alcohol, positional asphyxia/suffocation, hypoglycaemia or ketoacidosis [ 19 ].

Different authorities have different views on the lethal blood concentration associated with AAP, and range from 3.50 to 4.00 mg/mL [ 4 , 20 ]. The mean BAC in 175 fatal cases recorded by Heatley and Crane [ 21 ] was 3.55 mg/mL. As a result of differences between individuals, the lethal threshold of the BAC is undefined and seems to be lower than conventional acknowledgement [ 22 ]. Jones [ 23 ] stated that the BAC of a driver in Sweden was >5.00 mg/mL but he was alive. The lethal dose of alcohol is related to sex, age and genetic factors, though the speed of alcohol consumption, type of beverage and drinking habits can also exert influences. Li et al. [ 24 ] showed that, in AAP-related death, overweight drinkers showed more significant BAC levels for the heart and peripheral circulation than normal-weight drinkers. The BAC in the three cases in the present study was 5.28, 3.33 and 3.78 mg/mL, respectively. Because of the high BAC in Case 1 (5.28 mg/mL), there is little doubt that the cause of death was AAP. In Case 2, the deceased consumed a large amount of high-alcohol-concentration spirit, which may resulted in a decrease in alcohol tolerance. She had a history of coma before death, which confirmed that her BAC had reached a lethal concentration. In Case 3, the deceased was only 19 years of age. Compared with adults, adolescents are more sensitive and less tolerant to alcohol [ 13 ]. Further investigation revealed that the deceased drank quickly and had not slept for 2 days before the incident, which may have reduced his tolerance to alcohol. A history of intravenous-drip rescue was found in Cases 2 and 3, which may have led to the decline in the BAC. The relationship between alcohol intake and the BAC is expressed by the Widmark formula [ 25 , 26 ]:

where BAC represents blood-alcohol concentration in mass/mass unit; BWt represents the body weight (kg); A represents the quantity (g) of alcohol absorbed and distributed in all body fluids and tissues at the time the blood sample was taken; and the rho-factor differs in different individuals. This formula provides a preliminary inference of the BAC, and verifies the accuracy of the case investigation and BAC-test results.

Results of ethanol determination in specimens postmortem can be affected by several factors, of which putrefaction and diffusion of gastric contents postmortem are the most common [ 1 ]. Ensuring timely submission to the test after death and keeping corpses frozen to inhibit bacterial activity can reduce the interference of putrefaction postmortem. Currently, n-propanol is used as an internal standard. However, the theory has been invalidated that if the deceased did not have prior alcohol consumption, the ratio of alcohol/n-propanol in his/her blood should be <20 [ 14 ]. Therefore, the expected ratio of alcohol/n-propanol must be determined.

Ethyl glucuronide (EtG) and ethyl sulfate (EtS) are products of alcohol metabolism, and can be produced only by enzymatic metabolism from the body. Under some circumstances, analyses of these ethanol metabolites can be useful to estimate putrefaction postmortem. However, EtG has a long half-life and may be unstable at 30 °C or 40 °C if blood samples are stored without preservatives [ 14 ]. Therefore, EtG cannot show that alcohol consumption is related directly to the death, and is not suitable for highly putrefactive corpses.

The urine alcohol concentration (UAC) can help to analyze alcohol metabolism. The UAC/BAC ratio could help to ascertain if the absorption and distribution of alcohol in all fluids is complete. Usually, a low ratio (both mean and median, 1.18:1) suggests that alcohol has been absorbed and distributed completely [ 27 ].

Besides its watery nature, the vitreous humour is less affected by bacterial spread from the intestinal tract, which makes it undergo less putrefaction post-mortem and has less redistribution postmortem [ 1 ]. Therefore, it can be used as a substitute and reliable assessment if blood is deficient or if there is putrefaction or redistribution postmortem [ 28 ].

Our three cases were sent for autopsy and toxicology tests 10, 17 and 18 days after death but the bodies were frozen, and organ autolysis was not obvious according to histology. Thus, we consider the BAC results to be reliable. Usually, the liquor pericardii exhibits the highest alcohol concentration, followed by the left pulmonary vein, aorta, left heart, pulmonary artery, superior vena cava, inferior vena cava, right heart, right pulmonary vein and femoral vein, in decreasing order [ 29 ]. Therefore, taking femoral venous blood simultaneously for a BAC test may help reduce the error from diffusion of gastric contents.

In fatal cases of AAP, detection of other drugs is not infrequent, of which diazepam is predominant [ 30 ]. Alcohol can interact with other drugs and promote their toxicological effects. Studies have shown that alcohol consumption increases the risk of death for heroin users [ 31 ]. Methamphetamine and cocaine can enhance the toxicological effects of alcohol [ 32 ]. Meanwhile, the BAC decreases if the number of other drugs in blood increases, which has an impact on results [ 33 ]. There are cases of death due to alcohol combined with other poisons (e.g. injecting drugs while consuming alcohol). Indeed, some criminals taint alcoholic beverages to commit crimes. In China, there is a tradition of drinking medicated wine, which may contain toxic components such as venin or aconitine [ 34 ]. Therefore, for cases of death due to AAP, routine toxicology tests should be done to exclude the possibility of death by other poisons. There are many types of toxic substances, so some rare toxic substances may be omitted from routine toxicology analysis. Thus, it is necessary to combine the autopsy, case details, and the crime-scene investigation with toxicology tests to make a comprehensive analysis. In all three cases, routine toxicology tests were carried out, and we did not find other meaningful discoveries through case investigation and autopsy. Therefore, other poisons could be excluded from the causes of death.

In recent years, extensive studies have interpreted how alcohol-induced inhibition of the respiratory centres in the brainstem help explain the cause of AAP-related death. Acute exposure to alcohol can influence synaptic transmission, break the delicate balance between excitatory and inhibitory neurons in the CNS, and inhibit brain functions by altering cell membranes, ion channels, enzymes, neurotransmitter receptors, and the proteins involved in intracellular signal transduction [ 35 , 36 ]. In pre-synaptic signalling, the main function of alcohol is to increase the release of γ-aminobutyric acid (GABA). According to in vivo and in vitro studies, alcohol intake can increase the GABA concentration significantly in some brain regions (amygdala, hippocampus, brainstem) and cause a dose-dependent increase in GABA release in Purkinje cells [ 37 , 38 ]. Recent studies have suggested that release of intracellular calcium, protein kinase A (PKA), protein kinase C (PKC) and adenylate cyclase have roles in this increase in the GABA concentration [ 39 ]. In post-synaptic signalling, alcohol acts mainly on neurotransmitter receptors and affects their functions. Alcohol has a non-competitive inhibitory effect on N -methyl- d -aspartic acid receptors, which are highly sensitive to acute exposure to alcohol by inhibiting calcium influx [ 40 ]. Furthermore, alcohol can strengthen the affinity between GABA and GABA receptors, increase influx of chloride ions, and enhance the long-term depression of GABA A receptors [ 41 ]. Experiments have shown that PKC is necessary for the alcohol-induced potentiation of GABAergic function, and that PKCσ plays an important part in activation of σ-subunit-containing GABA A receptors [ 41 , 42 ]. Alcohol can also act directly on the hydrophobic domain of 5-hydroxytryptamine-3 (5-HT 3 ) receptors, where it makes the opening of these channels more stable, potentiates the function of 5-HT 3 receptors and, eventually, enhances CNS depression [ 43 , 44 ].

As stated above, the forensic appraisal of AAP-related death should pay attention to four main features. First, the case information must be considered, detailed questioning of witnesses should be conducted, and the scene should be surveyed carefully. People who have died due to AAP often have a history of alcohol abuse. Empty or partially empty bottles of alcoholic beverages — or even vomit — can be found at the scene of death. Investigators should pay attention to and collect suspicious items, such as physical evidence on the body and clothing of the deceased. If there is suspicion that the deceased had consumed adulterated wine or medicinal liquor or had been poisoned with toxic substances other than an alcoholic beverage, all of the edible food, drink, and vomit should be sealed and sent for testing. Data from video surveillance can, in some cases, help clarify the activities of the deceased and other details. The second feature is a complete and detailed autopsy. Suspicious injuries or abnormal body conditions/phenomena postmortem should be looked for. AAP-related death exhibits asphyxiation and excludes other causes of death, such as mechanical injury, mechanical asphyxia or electrocution. The third feature is common forensic toxicology testing (e.g. BAC). To eliminate interference by diffusion of gastric contents, blood from the femoral vein should be taken for toxicology testing. Samples of urine and the vitreous humour can be taken simultaneously, if necessary. For highly putrefactive corpses, extraction of the vitreous humour can be attempted for testing [ 45 ]. Meanwhile, routine toxicology tests should be carried out and combined with the case investigation and autopsy. The toxicological effects of different drugs and their blood concentration should be analyzed to determine the true cause of death and the potential role of alcohol. The final feature is a comprehensive analysis of various factors. When considering deaths after alcohol intake, investigators should not simply classify these cases as AAP-related death based on their first impressions, but instead should exclude other suspicious factors to ensure a strict and accurate forensic appraisal.

Authors’ contributions

Hui Wang drafted the manuscript; Hongmei Xu helped to draft the manuscript and polished the language; Wencan Li, Beixu Li and Qun Shi carried out the autopsy of three cases; Kaijun Ma and Bi Xiao helped to collate three cases; Long Chen conceived of the manuscript and helped to draft the manuscript. All authors contributed to the final text and approved it.

Compliance with ethical standards

All procedures undertaken in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee, and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. We declare that the present study complies with current Chinese law. Informed consent was obtained from each individual's family in this study.

Disclosure statement

The authors declare that they have no conflict of interest.

Environmental Medicine: Integrating a Missing Element into Medical Education (1995)

Chapter: case study 23: methanol toxicity.

20 Methanol Toxicity

This monograph is one in a series of self-instructional publications designed to increase the primary care provider’s knowledge of hazardous substances in the environment and to aid in the evaluation of potentially exposed patients. See page 21 for more information about continuing medical education credits and continuing education units.

U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

Agency for Toxic Substances and Disease Registry

A 67-year-old man with headache, nausea, and visual disturbance

During an afternoon visit, you see a 67-year-old man for onset of headache, nausea, and visual disturbance. The friend who accompanies him explains that both of them frequent the same senior center and that they have been preparing for a fund-raising event during the past 2 days. During this time, the patient spent between 6 and 9 hours per day reproducing fliers using a “spirit duplicator” (mimeograph machine). This activity took place in a small, unventilated room with the patient working alone most of the time.

On questioning, the patient says that he had eye irritation and lightheadedness after the first few hours of activity but considered these symptoms to be a minor annoyance. He also had nausea by the end of the first day but noted that this cleared overnight. During the second day of activity, he was again troubled by eye irritation, this time accompanied by vertigo, tinnitus, visual blurring, and photophobia. He tried to ventilate the room by placing a small fan near the door but continued to feel poorly despite a prolonged break. Late in the afternoon his friend insisted that he seek medical attention.

The patient is a widower and retired insurance salesman with a smoking history of one pack per day from age 27 to 62 (none for the last 5 years). He typically consumes a six-pack of beer per day, but he has felt poorly and has been abstinent for the past 10 days. Medical history includes coronary artery bypass surgery at age 63 with subsequent medical management of stable angina and a transurethral prostatectomy at age 65 with no recurrence of obstructive symptoms. Current medications include nitroglycerine patches used before exercise (with no patches used in the previous 4 days) and sublingual nitroglycerine, which he takes rarely. The review of symptoms is negative for other cardiopulmonary complaints. There is no family history of glaucoma, myopia, or diabetes mellitus.

On examination, the patient is alert and oriented to time, space, and person, although he appears somewhat distracted. His breath has a faint solvent-like smell. Vital signs are within normal range with the exception of a respiratory rate of 30/minute. The cardiopulmonary examination is unremarkable, but abdominal examination reveals mild tenderness in the epigastrium without rebound or guarding. Muscle tone, strength, sensation (pinprick, light touch, position sense) and reflexes are symmetrically intact. His gait is unsteady with a wide-based stance, and he shows a positive Romberg sign, heel-to-shin, and rapid alternating movements (bilaterally).

Ophthalmologic examination reveals a visual acuity of 20/200 bilaterally despite newly prescribed corrective lenses. The conjunctivae appear somewhat injected, nystagmus is present on lateral gaze, and the pupils are large and poorly reactive to light. Examination also reveals hyperemia of the optic nerve head with no hemorrhages or exudates.

(a) What is the differential diagnosis for this patient?

_________________________________________________________________

(b) What additional information would you request regarding the patient’s activities in the last 2 days?

(c) What consultation(s) would you obtain to help you manage this case?

(d) What type of therapeutic intervention is indicated?

Answers can be found on page 17.

Exposure Pathways

❑ Methanol is used in a variety of commercial and consumer products.

❑ Increased use of methanol as a motor fuel may cause higher ambient air levels and a greater potential for ingestion from siphoning accidents.

Methanol (methyl alcohol) is a clear, colorless, flammable liquid with a faintly pleasant odor. Popularly known as wood alcohol, methanol has historically been referred to as wood spirit, wood naphtha, pyroligneous spirit, and carbinol. Despite these references to its derivation as a wood distillation product, methanol is currently produced almost exclusively by synthetic pathways. It ranks 22nd (by volume) among chemicals produced in the United States.

The largest quantities of methanol are used for the manufacture of other chemicals including methyl methacrylate, acetic acid, ethylene glycol, and methyl chloride. Methanol also is added to a variety of commercial and consumer products such as windshield washing and deicing solutions (35% to 95% concentration), duplicating fluids (95% concentration or greater), solid canned fuels (4% concentration), paint removers, model airplane fuels, and embalming fluids. Other methanol uses are as a denaturant for ethanol; as a solvent for shellacs, lacquers, adhesives, and inks; and, most recently, as an alternative motor fuel. Because methanol is a natural fermentation product, its concentration may be up to 300 milligrams per liter (mg/L) in wines and higher in brandies and other distilled fruit spirits. Although serious methanol toxicity has been most commonly associated with ingestions, exposures also occur via inhalation and skin absorption, which are a concern in both occupational and household settings.

Environmentally, methanol has been detected in concentrations ranging from less than 10 parts per billion (ppb) in rural air to nearly 30 ppb in urban air. If methanol-powered vehicles become more prevalent, ambient methanol levels could be thousands of times greater in residential and public parking garages. Currently, there is no enforceable atmospheric standard for methanol. Increased use of methanol as a motor fuel would probably result in the reduction of some air pollutants (e.g., particulates and ozone) but an increase in others (e.g., formaldehyde). Data regarding methanol levels in drinking water are lacking.

Who’s at Risk

❑ Persons having prolonged skin contact with methanol are at risk of developing severe systemic effects.

❑ Persons ingesting adulterated alcoholic beverages are at great risk of methanol toxicity.

❑ Folate-deficient persons are potentially at increased risk for toxicity after methanol exposure.

According to estimates from the National Institute for Occupational Safety and Health (NIOSH), more than 2.5 million persons are regularly exposed to methanol on the job. Workers most likely to experience inhalation or skin exposures to methanol include bookbinders, bronzers, dyers, foundry workers, gilders, hatmakers, ink makers, laboratory technicians, painters, photoengravers, and chemical manufacturers. In addition, administrative aides or others using mimeograph machines may be exposed to methanol, as well as workers at refineries, fuel distribution centers, and service stations, if they handle methanol-containing fuels.

Householders, hobbyists, and motorists using methanol-containing products can be at risk for inhalation exposure; therefore, precautions must be taken to avoid using these products in poorly ventilated spaces. In addition, prolonged skin contact with methanol can produce systemic effects—a painter developed blindness after working in methanol-soaked clothes, and an 8-month-old child with a methanol-soaked pad placed on his chest developed signs of methanol toxicity.

Historically, the largest number of serious methanol exposures have occurred by ingestion. Methanol poisoning has been caused by materials such as shellac thinner, duplicator fluid, and denatured alcohol that have been drunk directly or have been used to adulterate beverages. In addition, about 35,000 gasoline ingestions are reported annually in the United States, most of which occur from fuel siphoning. Siphoning accidents could significantly increase the number of methanol ingestions if the use of methanol-containing automotive fuels becomes widespread.

One step in the metabolic detoxification of methanol is a folic acid-dependent process. Consequently, susceptibility to methanol toxicity may be higher among folate-deficient persons. Folate deficiency can occur not only in persons consuming inadequate diets, but also in those with intestinal malabsorption (e.g., inflammatory bowel disease) or hemolytic anemia, or in persons undergoing drug therapy (e.g., anticonvulsants, antibiotics). Because alcoholics have a greater likelihood of both methanol ingestion and folate deficiency, they may be at dual risk for methanol’s adverse effects. Up to 10% of the population may be folate-deficient.

Biologic Fate

❑ Methanol is absorbed well by all exposure routes.

❑ Methanol is oxidized in the liver to formaldehyde, then formic acid, which contributes to the profound metabolic acidosis seen in acute methanol poisoning.

❑ Most methanol is eliminated via the lungs as carbon dioxide.

Gastrointestinal absorption of methanol is virtually complete, whereas lung retention averages 58%. Dermal absorption may occur if skin is abraded or methanol exposure is prolonged. There is evidence that methanol absorption through the skin is enhanced in gasoline-methanol mixtures. Once absorbed, methanol is distributed with total body water.

Metabolism of methanol is a three-step process taking place chiefly in the liver. The first metabolic step involves methanol’s oxidation to formaldehyde by alcohol dehydrogenase, which is a saturable, rate-limiting process ( Figure 1 , Step 1). In the next step ( Figure 1 , Step 2), formaldehyde is oxidized by aldehyde dehydrogenase to formic acid (or formate, depending upon pH). Since step 2 is rapid, little formaldehyde accumulates in the serum. Formic acid, a metabolite of formaldehyde, contributes to the development of metabolic acidosis both directly (i.e., via its acid load) and indirectly (i.e., through its inhibitory effects upon iron-containing cytochromes with subsequent accumulation of lactic acid [lactate]). In Step 3, formic acid is detoxified to carbon dioxide and water.

Some absorbed methanol is eliminated unchanged via the lungs (10% to 20%) and kidneys (about 3%). However, most absorbed methanol is oxidatively metabolized (75% to 85%). A small amount of the metabolic products is excreted in the urine as formate, but most is exhaled as carbon dioxide. Methanol elimination patterns are dose-dependent, with elimination half-lives ranging from 3 hours in volunteers who ingested small amounts of methanol to 30 hours in persons who overdosed.

Figure 1 . Methanol metabolism to toxic intermediates—formaldehyde and formic acid (formate).

Discovery of methanol’s metabolic pathway has led to several practical treatments; among them are the therapeutic administration of ethanol and folic acid. Alcohol dehydrogenase, the enzyme responsible for the first step of methanol metabolism, has an approximately ninefold greater affinity for ethanol than for methanol. Administration of ethanol blocks the oxidation of methanol, preventing the lethal synthesis of formaldehyde and formic acid and increasing the amount of methanol that is eliminated unchanged (now approximately equal amounts in urine and exhaled breath). Administration of folic acid and its analogues, which affect Step 3, enhances the conversion of toxic formic acid to carbon dioxide and water ( Figure 1 ).

Physiologic Effects

Acute exposure.

❑ The acute effects of inhaling methanol vapor, which are similar to those caused by many other organic solvents, include upper respiratory tract irritation and inebriation.

Methanol shares with many other hydrocarbon solvents the ability to produce reversible sensory irritation, headache, nausea, and narcosis at airborne levels below those producing specific organ system pathology. Headaches were a frequent complaint in one study of office workers in the vicinity of duplicating machines where airborne methanol levels were in the range of 200 to 375 parts per million (ppm). In another study, exposed administrative aides were

❑ The metabolic products of methanol can produce a syndrome of delayed-onset acidosis, obtundation, visual disturbance, and death.

❑ Partial or total blindness, dementia, or a Parkinson-like syndrome are potential sequelae in survivors of acute methanol intoxication.

significantly more likely to report blurred vision, headache, dizziness, and nausea than were controls. Workers reported that the symptoms improved when they were away from the workplace.

Most methanol-related metabolic and ophthalmologic alterations have been associated with exposure through ingestion. Although the most frequently cited dosage for a lethal methanol ingestion is 1 milliliter per kilogram (mL/kg) of body weight, permanent blindness and deaths have been reported with ingestions as low as 0.1 mL/kg (6 to 10 mL in adults).

Metabolic Effects

After a characteristic latent period of 6 to 30 hours, severe metabolic acidosis may occur in victims of methanol poisoning. The acidosis is due to formic acid, and less often, lactic acid. Formic acid is metabolically produced from methanol, while lactic acid results from hypotension and from formate’s interference with cellular respiration.

Ophthalmologic and Neurologic Effects

Experimental evidence suggests that formate is responsible for optic nerve damage in methanol overexposure. In fatal cases, the optic nerve shows central necrosis in the distal (orbital) portion with the central optic tracts intact. In nonfatal cases, visual function can normalize completely after treatment, although central and peripheral scotomata or complete blindness may persist, depending on several variables. Occasional neurologic sequelae of methanol poisoning can include polyneuropathy, a Parkinson-like extrapyramidal syndrome, and mild dementia. Hemorrhages in the putamen have been documented on computerized tomography (CT) scanning and on pathologic examination.

Chronic Exposure

Respiratory and ophthalmologic effects.

❑ Chronic exposures to methanol have not been thoroughly studied, although anecdotal reports of chronic visual effects have been published in the medical literature.

Despite methanol’s widespread use, there are few rigorous studies of workers chronically exposed to methanol. Some reports can be found of permanent visual effects due to chronic inhalation or dermal exposure, but many of these reports date to the early part of the century and lack exposure data. Inhalation studies in experimental animals do not demonstrate significant pathology with chronic exposures at levels up to 50 times the current occupational Permissible Exposure Limit (PEL) of 200 ppm. The only consistent effects in rats and monkeys exposed for 4 weeks to levels up to 5000 ppm methanol vapor were mucoid nasal discharge and upper respiratory tract irritation; no ophthalmologic alterations were found. Because formic acid is rapidly metabolized and does not accumulate in

experimental animals, they may not be good models for the ophthalmologic effects of methanol.

Other Effects

❑ Data regarding the potential developmental effects of methanol exposure are inconclusive.

❑ Data regarding the carcinogenic potential of methanol in humans are lacking.

Published data on animal and human developmental effects of methanol are limited and inconclusive. One case-control study of pregnant women in the workplace shows a possible association of fetal central nervous system defects with exposures to a mixed solvent that included methanol. The general medical literature contains no references to methanol’s carcinogenic potential in humans.

Clinical Evaluation

History and physical examination.

❑ In cases of suspected methanol intoxication, the goal is to determine exposure route and neurologic and ocular status.

History-taking in methanol intoxications should focus on exposure route. In suspected ingestions, the clinician should ask about the consumption of illicit alcoholic beverages (or beverages that may have been adulterated) and about other potential accidental or intentional ingestion scenarios. In suspected inhalational and dermal exposures, emphasis should be placed on identifying specific methanol-containing products (e.g., canned fuel, windshield washer solution, duplicator fluid, shellac thinner, alternative fuels) and on documenting unusual conditions of prolonged and extensive skin contact or inhalation. The symptom history should emphasize disturbances in visual, neurologic, and gastrointestinal function. The physical examination should focus particularly on neurologic status and ocular findings.

Signs and Symptoms

❑ Timely evaluation of a patient who may be over-exposed to methanol is essential to prevent severe and permanent sequelae.

Persons acutely exposed to high levels of methanol via ingestion, inhalation, or extensive skin contact may develop severe metabolic, ocular, and neurologic toxicity. The initial intoxicating effects of methanol are similar to those of ethanol in producing cognitive slowing and cloudy sensorium, which extends to impaired brain stem function at very high doses. After a latent period of 12 to 24 hours, methanol toxicity may result in progressive visual disturbance and impairment of consciousness due to the gradual build-up of toxic metabolites. Unusual ocular symptoms, such as a sensation of “being in a snowstorm,” may be reported. Ophthalmologic examination may reveal central or peripheral visual field defects and dilated pupils that react poorly to light but accommodate normally. Erythema of the optic nerve may occur, with peripapillar edema early in the course. Rarely, flame-shaped hemorrhages may be seen. Necrosis of the distal portion of the optic nerve leads to atrophy, which may be evidenced by optic nerve pallor days or weeks after exposure.

❑ Symptoms of chronic, low-level methanol exposure are generally reversible.

Persons intermittently or chronically exposed to airborne methanol at levels insufficient to cause systemic acidosis may complain of eye irritation and visual blurring, upper respiratory irritation, headache, nausea, and lightheadedness—all of which are reversible under these conditions. Chronic short-term cutaneous exposures may result in skin irritation and defatting. Chronic ingestion of methanol at levels documented in commercially distilled beverages or in drinking water have not been linked with specific symptoms or pathology.

Laboratory Tests

In light of methanol’s profound metabolic effects, numerous standard laboratory tests are useful in documenting acute toxicity. These include the following:

Blood methanol and blood ethanol

Arterial blood gases

Serum electrolytes (Na + , K + , Cl − , HCO 3 − ) and calculation of anion gap

BUN and serum creatinine

Serum glucose

Serum ketones

Serum osmolarity and calculation of osmolar gap

Direct Biologic Indicators

❑ Immediately after an acute exposure, a blood methanol level serves as the best predictor of the severity of the clinical course.

❑ Chronic methanol exposure can be documented by measuring urinary methanol.

Although methanol can be detected in both urine and exhaled breath, blood methanol levels are more widely available and serve as the best predictor of toxicity immediately after acute exposure. The normal blood concentration of methanol from endogenous sources is less than 0.05 milligrams per deciliter (mg/dL). Generally, central nervous system effects appear above blood methanol levels of 20 mg/dL; ocular symptoms appear above 100 mg/dL; and fatalities in untreated patients have occurred in the range of 150 to 200 mg/dL.

After the latency period, blood methanol level alone is not a reliable prognostic indicator because toxicity results from the metabolites. A methanol level below 20 mg/dL in a symptomatic patient, for example, does not rule out serious intoxication since the methanol may already have been completely metabolized to formate. When considerable time has elapsed after ingestion, mortality correlates best with severity of acidosis rather than with blood methanol levels.

In the workplace, where intermittent or chronic exposures are likely to occur, the American Conference of Governmental Industrial Hygienists (ACGIH) recommends a urinary methanol level of less than 15 mg/L at the end of an 8-hour workshift.

Indirect Biologic Indicators

❑ Formate levels are useful as indicators of methanol exposure, although they are not widely available.

❑ Both the anion and osmolar gaps are increased in methanol poisoning.

Of methanol’s metabolites, only formate is present in biologic fluids at concentrations useful for monitoring exposures. When serum formate levels exceed 20 mg/dL, ocular injury and metabolic acidosis are likely. In acute intoxications, elevated serum formate concentrations can confirm the diagnosis and aid in clinical decisionmaking regarding the institution of hemodialysis. However, laboratory tests for serum formate levels are not widely available.

The ACGIH considers a urinary formic acid level of less than 80 milligrams per gram (mg/g) creatinine, obtained preshift at the end of a workweek, as indicative of exposures below the 8-hour time-weighted average (TWA) of 200 ppm.

The anion gap and osmolar gap aid in the diagnosis of acute methanol poisoning. The serum anion gap (AG) may be defined by the formula

AG=(Na + +K + )−(Cl − +HCO 3 − )

with all ions measured in milliequivalents per liter (mEq/L). The normal anion gap is 12 to 16.

An approximation of the serum osmolar gap (OG) is most commonly defined as

OG=Osmolarity (measured)−(2 Na + +[BUN+2.8]+[Glucose+18])

with measured osmolarity expressed in milliosmoles per liter (mOsm/L), Na + in mEq/L, and BUN and glucose in mg/dL. The normal osmolar gap is 0 to 10.

The conditions that can produce an elevated anion-gap acidosis are summarized by the mnemonic MUDPILES:

Of the various pathophysiologic states and toxic agents listed above, only diabetic ketoacidosis, ethanol ketoacidosis, and methanol and ethylene glycol poisoning produce elevations of both the anion and osmolar gaps. Identification of diabetic ketoacidosis is based on the findings of elevated serum glucose and ketones, particularly in a person with pre-existing diabetes mellitus. Ethanol ketoacidosis is characterized by a history of chronic, excessive ethanol intake with anorexia and vomiting and acidosis out of proportion to the apparent degree of ketonemia.

Differentiation of methanol and ethylene glycol poisoning is based on the exposure history and on specific toxicologic testing. In ethylene glycol poisoning, there is an absence of eye complaints; oxalate crystals are found in the urine; and hypocalcemia may be present.

Findings that may accompany secondary complications of methanol poisoning include myoglobinuric renal failure (with elevations in serum creatinine and CPK, a positive test for occult blood in the urine, and rare or absent red blood cells in the urine sediment), pancreatic or salivary gland pathology (with hyperamylasemia), and central nervous system pathology (as evidenced by diffuse cerebral edema or hemorrhages of the putamen on CT scanning). Mean corpuscular volume (MCV) is elevated in severe methanol poisoning, probably resulting from a primary increase in red blood cell size from poisoning rather than megaloblastic anemia.

Treatment and Management

❑ With methanol poisoning, substantial treatment delays may occur because the clinician is falsely reassured by the initial lack of severe symptoms.

❑ Intravenous sodium bicarbonate therapy should be considered if the blood pH is below 7.2.

❑ Symptoms and history determine whether intravenous ethanol therapy and hemodialysis should be instituted.

Acute methanol Intoxication constitutes a medical emergency. Effective therapy requires attention to both clinical and laboratory data, as well as anticipation of events that may be latent at the time of initial examination. Methanol intoxication, like that of ethylene glycol, acetaminophen, and lithium, may deceive the clinician by the initial lack of severe toxic manifestations.

For recent, suspected methanol ingestions, gut decontamination should be carried out even in the absence of clinical or laboratory abnormalities. Emesis should be induced if the patient is conscious and if a substantial ingestion has occurred within 30 to 45 minutes of first medical care; alternatively, gastric lavage may be performed, particularly if the patient is obtunded. There is no evidence that activated charcoal or cathartics significantly reduce methanol absorption.

Formate’s diffusion across cell membranes, particularly in the optic nerve, is facilitated by a low systemic pH; hence, therapy should include partial correction of acidosis via direct alkalinization. Intravenous sodium bicarbonate therapy, which is aimed at reversing acidosis (by titrating the blood pH) to avert circulatory collapse and

impede the intracellular penetration of formic acid, should be considered if the pH is below 7.2. A reduction of blood pH of 0.15 corresponds to a base deficit of 10 mEq/L bicarbonate. The target should be a pH in the range of 7.36 to 7.40. Sodium bicarbonate solution should be administered slowly to allow the resulting carbon dioxide to dissipate via hyperventilation. Sodium overload is a constant hazard of sodium bicarbonate therapy, and electrolytes must be monitored frequently.

In cases of suspected methanol exposure, the following are indications for starting an intravenous ethanol infusion: a blood methanol level of greater than 20 mg/dL; a history of ingesting more methanol than 0.4 mL/kg body weight; any ingestion history, with delayed access to toxicologic testing; or metabolic acidosis with otherwise unexplained elevated anion and osmolar gaps, especially if eye symptoms are present. Ethanol, usually as a 10% solution (10 mL of 100% ethanol in 90 mL of 5% aqueous dextrose), is first administered intravenously in a loading dose of approximately 7.5 to 10 mL/kg over 20 to 60 minutes. If the patient is conscious, oral loading doses can be given since intravenous doses may be painful.

The subsequent ethanol infusion rate varies with the patient’s ethanol metabolism and should be adjusted to keep the blood ethanol level between 100 and 150 mg/dL. Typically, rates between 0.8 to 1.4 mL/kg/hr suffice. In chronic alcoholics and during hemodialysis (see paragraph below), higher rates may be required. Infusions are continued until the methanol level drops below 20 mg/dL.

Criteria for combined ethanol infusion and hemodialysis include visual disturbance, or a methanol level exceeding 50 mg/dL, or a severe acidosis unresponsive to intravenous bicarbonate. Peritoneal dialysis is less effective than hemodialysis in clearing methanol from the blood. During hemodialysis, ethanol infusions should not only continue, but also should be increased slightly to compensate for the increased ethanol clearance. Even during dialysis, the target blood ethanol concentration should remain at 100 to 150 mg/dL.

An adjunctive treatment for methanol poisoning is the administration of folate (in the form of folic acid or folinic acid) to increase the conversion of formate to carbon dioxide and water. Folate administration is considered safe and may be efficacious if the patient is folate-deficient. Suggested dosage regimens include folic acid, 50 to 70 mg intravenously every 4 hours for the first 24 hours of treatment, or folinic acid (also known as leucovorin, Citrovorum factor, or 5-formyl-5,6,7,8-tetrahydrofolate), 1 to 2 mg/kg intravenously every 4 to 6 hours. Any attempt to replenish folic acid stores by administering multiple vitamins is likely to be frustrated by their low folate content (typically 1 mg per tablet).

An experimental drug, 4-methylpyrazole, is being investigated in animals and humans. This orally administered drug, which combines with the enzyme alcohol dehydrogenase, may replace ethanol as a

safe means to block methanol metabolism while patients are prepared for hemodialysis. Administration of 4-methylpyrazole does not appear to add to the patient’s CNS depression as does ethanol. In addition, the metabolism of 4-methylpyrazole is more predictable and prolonged than is that of ethanol, making administration less difficult technically. Investigation of 4-methylpyrazole is currently in Phase I in the United States.

❑ Patients chronically exposed to methanol should be treated symptomatically.

Because a clearly defined clinical syndrome does not exist for chronic methanol exposure, treatment should be symptomatic. Patient management should include removal from exposure, supportive counseling, and a consideration of alternative diagnoses.

Standards and Regulations

❑ Currently, EPA does not regulate the amount of methanol in public drinking water supplies.

❑ EPA has not promulgated an air emission standard for methanol.

❑ OSHA regulations for worker exposures to methanol include a requirement that skin contact be minimized.

Methanol is volatile at room temperature and has an odor threshold at approximately 100–250 ppm concentration in air. The Occupational Safety and Health Administration (OSHA) maintains a workplace limit for airborne exposures to methanol of 200 ppm (as an 8-hour TWA) and 250 ppm for short-term (15-minute) excursions not to exceed four such excursions in an 8-hour day ( Table 1 ). Identical standards are recommended by ACGIH and NIOSH. The odor of methanol may not be perceived by some persons until levels exceed acceptable workplace limits. Concentrations exceeding 25,000 ppm are considered “immediately dangerous to life or health” (i.e., they may result in irreversible health effects or impair the ability of an individual to escape from the exposure environment). In general, airborne exposures can be controlled through engineering measures or by appropriate personal protective equipment or both.

Significant dermal absorption of methanol can occur. Workers using methanol should be protected against dermal exposures by engineering controls (e.g., by isolating the work process) and by using personal protective equipment (impervious gloves, aprons, boots, and other appropriate equipment).

Environment

EPA does not have an emission standard for methanol. However, under EPA’s generic standards for the synthetic organic chemical manufacturing industry, all volatile organic chemical (VOC) emissions, including methanol releases, are to be kept to a technologically feasible minimum.

Drinking Water

Neither EPA nor the states maintain standards for methanol in drinking water.

Table 1 . Standards and regulations for methanol

Suggested Reading List

Environmental Sources and Routes of Exposure

Bindler F, Voges E, Laugel P. The problem of methanol concentration admissible in distilled fruit spirits. Food Addit Contam 1988;5:343–51.

Frederick LJ, Schulte PA, Apol A. Investigation and control of occupational hazards associated with the use of spirit duplicators. Am Ind Hyg Assoc J 1984;45:51–5.

Kahn A, Blum D. Methyl alcohol poisoning in an 8-month-old boy: an unusual route of intoxication. Pediatrics 1979;94:841–3.

Diagnosis and Treatment

Becker CE. Methanol poisoning. J Emerg Med 1983;1:51–8.

Ekins BR, Rollins DE, Duffy DP, Gregory MC. Standardized treatment of severe methanol poisoning with ethanol and hemodialysis. West J Med 1985;142:337–40.

Enger E. Acidosis, gaps and poisonings [Editorial]. Acta Med Scand 1982;212:1–3.

Gonda A, Gault H, Churchill D, Hollomby D. Hemodialysis for methanol intoxication. Am J Med 1978;64:749–58.

Jacobsen D, Bredesen JE, Eide I, Ostborg J. Anion and osmolal gaps in the diagnosis of methanol and ethylene glycol poisoning. Acta Med Scand 1982;212:17–20.

Jacobsen D, McMartin KE. Methanol and ethylene glycol poisonings. Mechanism of toxicity, clinical course, diagnosis and treatment. Med Toxicol 1986;1:309–34.

Osterloh JD, Pond SM, Grady S, Becker CE. Serum formate concentrations in methanol intoxication as a criterion for hemodialysis. Ann Intern Med 1986;104:200–3.

Suit PF, Estes ML. Methanol intoxication: clinical features and differential diagnosis. Cleve Clinic J Med 1990;57:464–71.

Complications of Intoxication

Aquilonius SM, Askmark H, Enoksson P, Lundberg PO, Mostrom U. Computerised tomography in severe methanol intoxication. Br Med J 1978;2:929–30.

Eckfeldt JH, Kershaw MJ. Hyperamylasemia following methyl alcohol intoxication. Source and significance. Arch Intern Med 1986;146:193–4.

Grufferman S, Morris D, Alvarez J. Methanol poisoning complicated by myoglobinuric renal failure. Am J Emerg Med 1985;3:24–6.

McLean DR, Jacobs H, Mielke BW. Methanol poisoning: a clinical and pathological study. Ann Neurol 1980;8:161–7.

Ley CO, Gali FG. Parkinsonian syndrome after methanol intoxication. Eur Neurol 1983;22:405–9.

Phang PT, Passerini L, Mielke BH, Berendt R, King EG. Brain hemorrhage associated with methanol poisoning. Crit Care Med 1988;16:137–40.

Rastogi SP, Gold RM, Arruda JA. Fanconi’s syndrome associated with carburetor fluid intoxication. Am J Clin Pathol 1984;82:124–5.

Related Government Document

National Institute for Occupational Safety and Health. Criteria for a recommended standard: occupational exposure to methyl alcohol. Washington, DC: US Department of Health, Education and Welfare, 1976; Publication no. (NIOSH) 76–148. NTIS no. P8–273 806/0.

Sources of Information

More information on the adverse effects of methanol and treating and managing cases of exposure to methanol can be obtained from ATSDR, your state and local health departments, and university medical centers. Case Studies in Environmental Medicine: Methanol Toxicity is one of a series. For other publications in this series, please use the order form on the back cover. For clinical inquiries, contact ATSDR, Division of Health Education, Office of the Director, at (404) 639–6204.

Answers to Pretest Questions and Challenge Questions

Pretest questions begin on page 1. Challenge questions begin on page 2.

Answers to Pretest

Acute visual loss in this age group can occur with central retinal artery or vein occlusion, internal carotid emboli, vitreous hemorrhage, retinal/macular hemorrhage, retinal detachment, temporal arteritis, cerebrovascular accidents of the posterior circulation, acute angle-closure glaucoma, idiopathic optic neuritis, head trauma, and carbon monoxide and methanol poisoning. Of these conditions, only cerebrovascular events, head trauma, temporal arteritis, and carbon monoxide and methanol poisoning commonly affect vision bilaterally. Other symptoms such as hyperpnea, and later, Kussmaul breathing, are indicative of acidosis (see page 10 for a differential diagnosis of acidosis). The patient also manifests signs of inebriation. Methanol poisoning could account for all of these effects.

The following information should be sought in any occupational or avocational history: (1) a full description of the activity in question, with identification of all chemical products used (including ethanol) either by chemical or trade name; (2) documentation of potential routes of exposure including inhalation, skin contact, and ingestion; and (3) type of ventilation employed and use of personal protective equipment.

Confirmation of suspected methanol poisoning should take place in an emergency department or inpatient setting with rapid laboratory tests and the opportunity for prompt therapeutic intervention. Physicians with special expertise who might be consulted in this case include clinical toxicologists, nephrologists, and ophthalmologists. In geographic areas with restricted access to specialists or with exposures of questionable toxicologic significance, informational assistance can be obtained from the nearest regional poison control center.

The clinical findings and the acknowledged methanol exposure (see Challenge question 2, page 4) are indicative of methanol intoxication of potentially life-threatening severity. Appropriate therapeutic interventions for methanol intoxication include intravenous ethanol infusion, sodium bicarbonate and folate administration, and hemodialysis.

In addition, the patient should receive psychosocial care for his substance abuse tendencies. Referral to a substance abuse program is appropriate.

Answers to Challenge Questions

In emergency situations, the most complete and up-to-date information is usually available through a regional poison control center. Common reference books that contain information on the chemical composition of consumer and commercial products include Gosselin’s Clinical Toxicology of Commercial Products and Sax’s Dangerous Properties of Industrial Materials, among others. Many local hospital emergency departments have access to toxicologic reference information either on microfiche or CD-ROM. Some hospital libraries also have access to online clinical toxicology databases.

The patient used a methanol-containing product for an extended period in a small, unventilated room. Thus, the inhaled dose alone is significant. The patient also admits to ingesting a small amount of the product. Furthermore, as an alcohol abuser, the patient may be folate-deficient, thus increasing his risk of methanol toxicity.

Yes, the symptoms and appearance of the patient in the case study do suggest acute methanol intoxication. The patient manifests symptoms of inebriation and complains of visual disturbance several hours after the start of a significant methanol exposure. He also is showing signs of acidosis. These factors constitute a classic presentation for acute methanol intoxication.

The calculated anion gap is 32 (normal: 12 to 16) and the calculated osmolar gap is 30 (normal: less than 10). These values are consistent with acute methanol intoxication. For calculations, see below.

Anion Gap=(Na + +K + )−(Cl − +HCO 3 − )

=(140+4)−(102+10)

=144−112

Osmolar Gap=Osmolarity (measured)−(2Na + +[BUN÷2.8]+[Glucose÷18])

=320−(2×140+[14÷2.8]+[90÷18])

=320−(280+5+5)

=320−290

Intoxication by the following agents (or accumulation, in the case of acetone in diabetic or alcoholic ketoacidosis) produces an elevated osmolar gap: methanol, ethanol, ethylene glycol, acetone, and isopropanol.

Although several drugs can potentially contribute to the osmolar gap (e.g., salicylates, paraldehyde, and chloral hydrate), they are rarely present at concentrations sufficient to raise osmolarity.

A neuro-ophthalmologic examination of the patient might reveal several findings. Results of examination of visual fields, as determined by perimetry, typically indicate central scotomata early in the course of methanol poisoning (soon after onset of acidosis), with peripheral constriction of visual fields a late finding. Dilated, unreactive pupils and dim vision are characteristic. The result can be bilateral blindness, which is usually permanent.

See the answer to Pretest question (d) above.

One-hundred proof vodka is actually 50% ethanol by volume. A loading dose equivalent to the required 7.5 mL/kg of 10% ethanol can be achieved with vodka as follows: In a 70 kg person, a total of 525 mL of 10% ethanol would be needed (7.5 mL/kg×70 kg=525 mL).

525 mL×10%=X mL×50%

52.5 mL=0.5X mL

X=105 mL of the 50% ethanol

In summary, 105 mL of 50% ethanol with 5% dextrose in water added to total 525 mL will produce a 10% ethanol solution. (See Treatment and Management , page 11.) This quantity of vodka or an equivalent amount of ethanol from another distilled spirit can be initially administered orally or by gavage.

People are increasingly concerned about potential environmental health hazards and often ask their physicians questions such as: "Is the tap water safe to drink?" "Is it safe to live near power lines?" Unfortunately, physicians often lack the information and training related to environmental health risks needed to answer such questions. This book discusses six competency based learning objectives for all medical school students, discusses the relevance of environmental health to specific courses and clerkships, and demonstrates how to integrate environmental health into the curriculum through published case studies, some of which are included in one of the book's three appendices. Also included is a guide on where to obtain additional information for treatment, referral, and follow-up for diseases with possible environmental and/or occupational origins.

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• Open access
• Published: 28 December 2018

Outcomes after toxic alcohol poisoning: a systematic review protocol

• Carol Wang 1 , 2 ,
• Daniel Samaha 2 , 3 ,
• Swapnil Hiremath 2 , 3 , 4 ,
• Lindsey Sikora 5 ,
• Manish M. Sood 2 , 3 , 4 ,
• Salmaan Kanji 4 &
• Edward G. Clark   ORCID: orcid.org/0000-0002-6767-1197 2 , 3 , 4  

Systematic Reviews volume  7 , Article number:  250 ( 2018 ) Cite this article

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Metrics details

Toxic alcohols have been implicated in accidental ingestions and intentional exposures. Recognition of toxic alcohol poisoning is challenging. The main treatment modalities include antidotes with alcohol dehydrogenase inhibitors and dialysis. Current guidelines exist for both methanol and ethylene glycol intoxication. However, treatment consensus related to other toxic alcohols is limited. Furthermore, uncertainties regarding thresholds for when to initiate antidotes and dialysis persist. As a consequence, variations exist in the interventions utilized for management of all toxic alcohol poisonings. To our knowledge, no prior systematic review of clinical outcomes of toxic alcohols exists. The objective of this study is to summarize existing evidence on short- and long-term outcomes of patients following toxic alcohol poisonings, including methanol, ethylene glycol, isopropanol, propylene glycol, and diethylene glycol.

A literature search in PubMed, MEDLINE, and EMBASE will be performed based on pre-determined criteria. There will be no restrictions on publication dates or languages. The search will be supplemented by manual scan of bibliographies of eligible studies and gray literature assessment. Observational studies and clinical trials will be included in this review. Once eligible studies have been selected based on pre-specified criteria, two investigators will extract relevant data independently and perform quality assessment per validated tools. A pooled analysis of mortality and short- and long-term secondary outcomes will be performed. Pre-specified subgroup analyses will be performed according to the type of toxic alcohol intoxication, mode of renal replacement therapy, and medical interventions received. A meta-analysis will be performed if three or more studies with similar populations, type of toxic alcohol poisoning, and outcome measures, as well as adequate quality, are identified. This review will be reported according to the recommendations of the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) Statement.

This systematic review aims to synthesize current evidence in the short- and long-term outcomes of post-toxic alcohol poisoning. The results will enhance the understanding of patient morbidity and mortality after toxic alcohol poisoning, help inform uniform concrete management guideline development, identify gaps in the current state of knowledge, and provide evidence to help implement post-treatment follow-up.

Systematic review registration

PROSPERO CRD42018101955

Peer Review reports

Toxic alcohols include methanol, ethylene glycol, isopropyl alcohol, diethylene glycol, and propylene glycol [ 1 , 2 ]. These alcohols have been implicated in accidental ingestions as well as intentional exposures in suicides and homicides [ 1 ]. They are readily obtainable through automotive and hardware stores as well as household detergents [ 1 ]. Between 2005 and 2014, methanol made up 5.7% while ethylene glycol constituted 5.9% of all intoxications managed with extracorporeal renal replacement therapy (ECRT) in Canada [ 3 ]. In the USA, approximately 50% of ECRTs performed over the same time period were for ethylene glycol, lithium, and salicylates intoxications [ 3 ]. Methanol poisoning was the most common indication for the management with renal replacement therapy amongst toxic alcohol intoxications, others of which include ethylene glycol, isopropanol, propylene glycol, and diethylene glycol [ 3 ].

Recognition of toxic alcohol poisoning is challenging due to non-specific clinical presentation and that patients are often unable to provide a history of exposure at presentation [ 1 , 2 ]. Clinical manifestations may evolve with the formation of toxic metabolites and are further compounded by co-ingestions [ 1 ]. Another element of challenge for diagnosis is a negative parent compound level in the serum if there is a delay in clinical presentation and the initial compound has been metabolized [ 1 ]. Prompt identification and initiation of therapy have important prognostic implications [ 4 ].

The toxicity of methanol and ethylene glycol arises from their respective metabolites while the parent compound is relatively innocuous [ 4 ]. The parent compounds of methanol and ethylene glycol are metabolized by alcohol dehydrogenase [ 1 ]. Formic acid is the breakdown product of methanol, which has the propensity to accumulate in the retina and basal ganglia to produce visual disturbances and blindness [ 1 , 2 ]. Ethylene glycol is eventually converted to oxalic acid, which causes renal and cranial nerve damage secondary to calcium oxalate deposition [ 1 , 2 , 5 ]. Metabolic acidosis and inebriation are common features of methanol and ethylene glycol metabolite toxicity [ 4 ]. The American Academy of Clinical Toxicology has outlined recommendations for antidote therapy with either ethanol or fomepizole as well as indications for hemodialysis [ 5 , 6 , 7 ]. Hemodialysis effectively removes both the parent compound and its toxic metabolites in addition to correcting metabolic disturbances [ 5 , 6 , 8 ].

In contrast to methanol and ethylene glycol, the toxicity of isopropanol arises from the parent compound [ 9 ]. Isopropanol is commonly found in rubbing alcohol and hand sanitizers and utilized as solvent or coating for industrial purposes [ 9 ]. Non-specific presentations associated with isopropanol poisoning include altered level of consciousness, respiratory depression, gastritis, acute pancreatitis, hypotension, and lactic acidosis [ 1 , 2 , 9 ]. Alcohol dehydrogenase inhibitors are contraindicated due to the associated accumulation of parent compound while its metabolite acetone is non-toxic [ 2 , 9 ]. Isopropanol is excreted by the kidneys and toxicity is mainly managed supportively, but hemodialysis is approximately 52 times more effective for the removal of isopropanol [ 1 , 9 ].

Propylene glycol and diethylene glycol toxicity are less commonly described in the literature. Propylene glycol is a common solvent for parenteral medications such as lorazepam, hence associated with high-dose infusion [ 10 ]. The compounds and their metabolites may precipitate metabolic acidosis and acute kidney injury [ 10 , 11 , 12 ]. Dialysis has been the main treatment modality for both toxicities while alcohol dehydrogenase inhibitor administration has been described in the literature for the management of diethylene glycol poisoning [ 10 , 11 , 12 , 13 ]. In some cases, hemodialysis has been initiated for the management of severe acidosis in the context of multiorgan failure due to propylene glycol and diethylene glycol intoxication for which treatment guidelines are not currently available [ 1 ].

Recommendations for the management of methanol poisoning have been put forth by the Extracorporeal Treatments in Poisoning (EXTRIP) workgroup and American Academy of Clinical Toxicology in the form of published guidelines for both methanol and ethylene glycol intoxications [ 5 , 6 , 7 ]. Unfortunately, it appears that the therapeutic benefits of hemodialysis are limited in cases where the toxic alcohols and metabolites have been metabolized and clinical sequelae are established [ 8 ]. Furthermore, consensus on thresholds for when to initiate alcohol dehydrogenase inhibitor and dialysis has yet been established [ 1 , 2 , 4 ]. Similar treatment guidelines and established standard of care have not been formulated for other types of toxic alcohols. Despite the presence of treatment guidelines for methanol and ethylene glycol poisoning, variations exist in their intervention strategies. For instance, the utilization of antidote monotherapy versus combination with renal replacement therapy, as well as the addition of adjunctive therapies such as folate in methanol poisoning and pyridoxine in ethylene glycol intoxication, is not standardized [ 1 , 4 ]. Ethylene glycol and methanol concentration thresholds at which fomepizole can be safely discontinued remain to be defined [ 4 ]. The vast majority of existing literature on toxic alcohol poisoning is in the form of observational studies and systematic reviews on its epidemiology, clinical presentations, and management. Although predictors for negative long-term consequences of toxic alcohol poisoning have been described [ 14 ], there is an overall paucity of data focusing on patient outcomes. Short-term patient outcomes have been mentioned as part of the reports focusing on clinical presentations and management of toxic alcohol poisoning instead of being the focus of studies. Individual observational studies with small sample sizes have examined the neurological and renal sequelae of methanol and diethylene glycol poisoning with variable lengths of follow-up ranging from 2 to 18 months [ 15 , 16 , 17 ]. To our knowledge, no prior systematic review of short- and long-term outcomes of toxic alcohols has been published. Toxic alcohol poisonings such as methanol intoxication continue to result in high morbidity and mortality likely due to the delayed presentation to medical care and challenges in establishing the correct diagnosis [ 18 ]. This article describes the protocol for a systematic review aimed at summarizing existing evidence on short- and long-term outcomes of adult patients following toxic alcohol poisoning.

The objective of this study is to summarize the existing evidence regarding short-term and long-term clinical outcomes of patients after toxic alcohol poisoning. The systematic review protocol is reported in accordance with the PRISMA-P 2015 Checklist (see Additional file  1 ). This protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) CRD42018101955. A public trial of amendments to this systematic review protocol will be reflected in PROSPERO.

Eligibility criteria

All studies that have reported on short-term and/or long-term outcomes of adult patients >  18 years old who presented with toxic alcohol poisoning are eligible. Both interventional and observational trials will be included. Case reports and case series consisting of less than or equal to five cases will be excluded. No restrictions will be placed on the study duration, study period, or date of publication. Furthermore, the pre-specified criteria detailed below must also be met.

Types of participants

We will include studies with patients 18 years of age or older diagnosed with toxic alcohol poisoning (specifically methanol, ethylene glycol, isopropanol, propylene glycol, and diethylene glycol poisoning). There are four groups of interest: (1) those treated with dialysis (this refers to extracorporeal interventions such as hemodialysis, continuous hemofiltration, hemoperfusion, continuous renal replacement therapy, and peritoneal dialysis, in this context), (2) those treated with specific antidote therapies fomepizole and/or ethanol, (3) those treated with both dialysis and specific antidote therapy, and (4) those treated with other medical treatments or supportive therapy only.

Exposure/intervention

The diagnosis of toxic alcohol poisoning may be made according to the presence of toxic alcohol(s) measured in the blood. Other criteria for toxic alcohol poisoning will also be included if they are clearly defined.

Clinical outcomes of interest are separated into short- and long-term, whereby short-term outcomes encompass clinically relevant end points (defined below) between the time of intoxication and hospital discharge. Long-term outcomes span up to 10 years post-hospitalization The primary outcome of interest in this systematic review is mortality at any time point reported. Short-term secondary renal outcomes include whether dialysis was undertaken for acute kidney injury due to toxic alcohol ingestion, type of dialysis, renal recovery at the time of hospital discharge, and duration of dialysis if renal recovery was achieved at discharge. Long-term secondary renal outcomes refer to ongoing dialysis dependence after hospital discharge, renal recovery post-discharge, duration of dialysis, and progression to end-stage renal disease requiring transplantation. Of note, renal recovery is defined as independence from renal replacement therapy [ 19 , 20 ]. Short-term toxin-associated complications include dependence on cardiopulmonary supports (such as assisted ventilation and vasopressors), altered level of consciousness, and duration of hospitalization. Both the short- and long-term toxin-mediated complications such as vision loss due to methanol, neurologic deficits, and cardiovascular events will also be recorded.

Search strategy

PubMed, MEDLINE (via Ovid), and EMBASE (via Ovid) were searched initially for prior systematic reviews that have addressed similar topics. PROSPERO was also searched to ensure a similar systematic review study protocols has not been registered. No prior studies of our topic of interest have been identified. The following databases will be searched by a health sciences librarian (LS) during the electronic component of the systematic review: MEDLINE and MEDLINE in Process (via OVID), EMBASE Classic + EMBASE (via OVID), Cochrane’s Central Registry for Randomized Controlled Trials, CENTRAL (via OVID), and PubMed. A search strategy will be developed in MEDLINE and then translated into the other databases, as appropriate (see Appendix ). All databases will be searched from the date of inception to July 3, 2018. There are no language exclusion criteria nor any other publication restrictions. All references will be entered into the citation manager, Endnote (version X9, Clarivate Analytics Inc., Philadelphia, PA), for processing. Supplemental searching will include a manual scan of the bibliographies of eligible studies, as well as gray literature searching in clinical trial registries such as clinicaltrials.gov and Google Scholar. The first three pages of the Google Scholar search will be screened for relevant titles. Studies will be screened by two reviewers (CW and EC) in the systematic review software, Covidence (Veritas Health Innovation LTD). Screening will occur at two levels: title/abstract and then full-text screening.

Study records

Data management.

Relevant data will be extracted from Covidence (Veritas Health Innovation LTD) and managed using Microsoft Excel. The first author will be responsible for the master copy. Comprehensive Meta-Analysis (version 2, Biostat) software will be used for data synthesis.

Data collection process

Two investigators (CW and EC) will screen the study titles and abstracts independently to determine eligibility for full-text assessment. The studies must meet the following criteria: (a) adult patients with toxic alcohol ingestion, including co-ingestions; (b) reported intoxication management (including both medical therapies and dialysis) and short-/long-term outcomes; (c) relevant studies of English and French languages will be included. Subsequently, the same investigators will examine the full texts to select those meeting the inclusion and exclusion criteria. Disagreements will be resolved with discussion until consensus is reached or involvement of a third investigator (SH).

Data extraction

A data extraction form will be created and populated with variables pertaining to the study population and primary and secondary outcomes of interest. The study characteristics of each eligible study including first author, publication year, location of study, study design, number of treatment arms, and follow-up duration will be tabulated. The age, gender, population size, and other baseline demographics such as baseline comorbidities and renal function (if known) will also be recorded. Patient characteristics include intoxicating agent(s), intention of intoxication (e.g., suicide, accidental), serum concentration of toxic alcohol, and time from ingestion/presentation to presentation for medical care. Factors associated with medical interventions include the interval between the time of ingestion to initiation of therapy, administration of antidotes, administration of elimination enhancement therapy (e.g., activated charcoal, gastric lavage), and criteria for proceeding to dialysis (ex. pH). When applicable, the study’s inclusion and exclusion criteria, if available, will also be sought.

In this systematic review, the short- and long-term mortality following toxic alcohol poisoning will be examined. In addition to secondary outcomes outlined above, other short-term secondary outcomes of interest include vasopressor dependence, respiratory failure requiring ventilatory support, renal failure, altered level of consciousness, and duration of hospitalization. Long-term outcomes such as renal recovery, toxin associated complications (for example, visual disturbances due to methanol), vision deficits, other neurologic defects, and cardiovascular events will also be recorded. One reviewer (CW) will collate the above data into Covidence (Veritas Health Innovation LTD) to be reviewed by a second author (EC).

Quality assessment

The quality of reporting and risk for bias of each included study will be assessed independently by two investigators (CW and EC). Disagreements will be resolved by consensus or involvement of a third reviewer if indicated. Observational studies will be evaluated in accordance with the Cochrane Risk of Bias Assessment Tool for Non-Randomized Studies of Interventions [ 21 ], and their quality of reporting will be assessed per Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Checklist [ 22 ]. Qualities of non-randomized trials will be examined per the Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool [ 23 ]. The Cochrane Handbook “Risk of Bias” assessment tool will be employed to assess any randomized controlled trials [ 24 ].

Data synthesis

For dichotomous outcome measures, we will calculate a pooled estimate of the proportion of patients across studies and the corresponding 95% confidence interval (CI). For continuous outcomes (e.g., time to dialysis discontinuation), we will calculate a pooled estimate of the mean and a corresponding 95% CI. Pooled analysis will be performed if three or more studies with adequate quality include similar populations, the same type of toxic alcohol intoxication, and outcome(s). The pooled analysis will be performed using the random effects model of DerSimonian and Laird [ 25 ]. Study level statistical heterogeneity will be examined utilizing the Cochran’s Q and the I 2 test [ 24 ]. If high statistical heterogeneity is detected (defined as > 75%), it will be explored using the subgroup analysis specified below. Publication bias will be assessed by visual examination of the funnel plot and using Egger’s test [ 26 ]. Pre-specified subgroup analyses will be performed based on the type of toxic alcohol poisoning, dialysis use, and medical intervention received. Type of alcohol poisoning will be assessed as a separate subgroup given that different types of alcohol poisoning have different pathophysiologic mechanisms and can be expected to have different outcomes [ 1 ]. In addition, the use of dialysis and other medical interventions (e.g., fomepizole treatment) is often employed in more severe cases in which worse outcomes might be expected than the overall patient population with toxic alcohol poisoning [ 1 ]. If sufficient intervention trials pertaining to the review topic are found and included, then an examination of the quality of evidence will be performed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria [ 27 ].

Potential limitations

We anticipate potential limitations to our review due to the likelihood that there will be a wide heterogeneity across the included studies with respect to the types of toxic alcohol poisoning, differences in reported outcomes, absence of comparator groups in many studies, and differences in patients’ characteristics at baseline. At the review level, we expect challenges with respect to the possibility that many studies will be case series in which case the selection of patients for inclusion is less likely to be representative of the overall population of patients with toxic alcohol poisoning.

Protocol amendments

Any protocol amendments will be clearly documented and justified with an addendum made to the protocol specifying the changes and their justification. In addition, any such changes and their justification will be included in the final report of the review.

Toxic alcohols are readily accessible in household and hardware stores [ 1 ]. Accidental and intentional poisoning through ingestion remains prevalent [ 3 ]. Understanding the mechanisms by which each alcohol imparts its toxicologic effects has aided in the development of antidotes and the role for renal replacement therapy (in particular, hemodialysis). However, there is likely variation in treatment practice due to the lack of robust consensus regarding thresholds for initiating medical therapies such as antidotes and renal replacement therapy [ 1 , 2 , 4 ]. In addition, little is known about long-term outcomes. This systematic review will examine the short- and long-term outcomes of patients after toxic alcohol poisoning and with respect to the treatments they did or did not receive. In doing so, we hope it will help shed light on the impact of various treatments on outcomes and help inform the optimal management and follow-up after toxic alcohol poisonings.

Abbreviations

Excerpta Medica dataBASE

Extracorporeal renal replacement therapy

Extracorporeal Treatments in Poisoning

Grading of Recommendations Assessment, Development and Evaluation

Medical Literature Analysis and Retrieval System Online

Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols

International Prospective Register of Systematic Reviews

Risk of Bias In Non-randomized Studies of Interventions

Strengthening the Reporting of Observational Studies in Epidemiology

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Acknowledgements

The authors acknowledge the institutional support of the Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.

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CW and EC generated the systematic review protocol and wrote the manuscript. LS provided assistance by executing the search strategies. All authors revised, read, and approved the final manuscript.

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Additional file

Additional file 1:.

PRISMA-P 2015 Checklist (DOCX 35 kb)

MEDLINE search strategy

exp. Renal Replacement Therapy/

((kidney* or renal) adj3 replacement adj2 therap*).tw.

exp. Renal Dialysis/

((renal or extracorporeal) adj2 dialys#s).tw.

exp. Hemofiltration/

h?mofiltration*.tw.

h?modialys#s.tw.

h?modialfiltration*.tw.

sustained low-efficiency dialysis.tw.

ethylene glycols/ or chloral hydrate/ or chloralose/ or ethylene glycol/ or methoxyhydroxyphenylglycol/ or polyethylene glycols/ or cetomacrogol/ or hydrogel, polyethylene glycol dimethacrylate/ or nonoxynol/ or octoxynol/ or poloxalene/ or poloxamer/ or polysorbates/

(toxic adj2 alcohol*).tw.

(ethylene adj2 glycol*).tw.

ethanediol*.tw.

hydroxyethanol*.tw.

(monoethylene adj2 glycol*).tw.

(diethylene adj2 glycol*).tw.

polyhydroxyethyl*.tw.

hydrogel*.tw.

(advantage adj S).tw.

(delfen adj cream*).tw.

(emulgen adj “911”).tw.

(emulgin adj “913”).tw.

methanol*.tw.

(chloral adj hydrate*).tw.

dihydroxyethane*.tw.

chloralose.tw.

anhydroglucochloral*.tw.

glucochloral*.tw.

cetomacrogol*.tw.

nonoxynol*.tw.

octoxynol*.tw.

poloxalene*.tw.

poloxamer*.tw.

polysorbate*.tw.

methoxyhydroxyphenylglycol*.tw.

methoxyphenylethyleneglycol*.tw.

(methoxyphenylethylene adj glycol*).tw.

vanylglycol*.tw.

(polyethylene adj2 (oxide* or glycol*)).tw.

macrogol*.tw.

polyoxyethylene*.tw.

triton*.tw.

polyethyleneoxide*.tw.

nonoxinol*.tw.

(patentex adj oral).tw.

pluronic*.tw.

proxanol*.tw.

octoxinol*.tw.

exp. Adult/ or (adult or adults or adulthood or middle age or middle aged or elderly or senior or seniors or man or men or woman or women).tw.

13 and 56 and 57

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Wang, C., Samaha, D., Hiremath, S. et al. Outcomes after toxic alcohol poisoning: a systematic review protocol. Syst Rev 7 , 250 (2018). https://doi.org/10.1186/s13643-018-0926-z

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11 Arrested in Fraternity Pledge’s Alcohol-Poisoning Death, Police Say

Adam Oakes, a 19-year-old student at Virginia Commonwealth University, died in February after being told to drink a bottle of Jack Daniel’s whiskey, family members say.

By Eduardo Medina

Eight people were arrested on Friday and three others on Monday after an investigation into the death of Adam Oakes, a student at Virginia Commonwealth University who died in February from alcohol poisoning at a fraternity party, the authorities said.

All 11 who were arrested face charges of unlawful hazing of a student, the Richmond, Va., police said in a statement. Six of them face an additional charge of buying and giving alcohol to a minor. All 11 are V.C.U. students, and nine of them were enrolled in the fall 2021 semester, according to a statement from the university.

According to Mr. Oakes’s family , the young man’s death, which drew national attention and renewed questions about hazing in Greek organizations across the country, occurred at an off-campus party on Feb. 26 at the Delta Chi fraternity house, where he was given a bottle of Jack Daniel’s whiskey and told to drink it.

Mr. Oakes, 19, was found dead the next morning by Richmond police officers, the authorities said.

Courtney White, Mr. Oakes’s cousin, said on Saturday that while the family was feeling “a little bit of relief” because the case was moving forward, it was still painful to know that nothing, including the charges, was “going to bring him back.”

“A lot of people are saying that these boys are just boys,” Ms. White said. “But the fact is that Adam was just a boy, too, and they took full advantage of him. And had any one of them stepped up and actually acted like a man and called for help, Adam would still be here.”

Family members said on Facebook that they were “grateful for some measure of justice these charges and arrests may produce, as well as the protection from hazing they may give young, impressionable college students.”

“The past 7 months have been agonizing for our family,” they wrote. “This is the first time these young men have been held accountable for their historically toxic and destructive traditions, manipulation of the VCU disciplinary systems, and for Adam’s death.”

The police named those arrested as Alexander Bradley, Benjamin J. Corado, Robert Fritz , Quinn A. Kuby, Riley K. McDaniel, Alessandro Medina-Villanueva, Jason B. Mulgrew, Christian G. Rohrbach, Colin G. Tran, Enayat W. Sheikhzad and Andrew White. They range in age from 19 to 22. Mr. Sheikhzad and Mr. White were not enrolled in the fall 2021 semester, V.C.U. said in a statement.

It was not clear on Saturday whether eight of them had lawyers. None could immediately be reached for comment on Saturday or Monday.

A website for Delta Chi listed Mr. Corado, Mr. Kuby, Mr. Medina-Villanueva, Mr. Mulgrew, Mr. Rohrbach and Mr. Tran as part of the V.C.U. chapter’s leadership team.

The university said in a statement that “V.C.U. continues to mourn the tragic death of Adam Oakes and is grateful to the Richmond Police Department for its investigation.”

“V.C.U. is dedicated to continuing its efforts, announced this summer, to promote a safe and welcoming fraternity and sorority life culture for all,” the university said.

The university also said that student privacy laws prohibited it from “sharing potential disciplinary information.”

V.C.U. permanently expelled Delta Chi from campus in May, after it hired a consulting firm to study its Greek culture. The firm, Dyad Strategies, announced in an August report that while the university wasn’t an outlier compared with other colleges’ Greek organizations, it still struggled to address concerns about binge drinking and hazing.

Seven of those arrested were taken into custody by the Virginia Commonwealth University Police and were being held without bond at the Richmond Justice Center. Mr. Sheikhzad was arrested by the Virginia State Police and released on bond.

Fraternity organizations have been under intense scrutiny in recent years, after high-profile cases that have drawn the ire of anti-hazing activists and victims’ loved ones who say that the culture of Greek life is dangerous and shrouded in secrecy . In 2017, Timothy Piazza, a student at Penn State University , died after he became drunk, fell and was left overnight by fraternity members who knew he needed help but failed to seek it.

Chun Hsien Deng, an 18-year-old freshman at Baruch College in New York City, died in 2013 after sustaining major brain trauma while taking part in a fraternity hazing ritual.

“Bullying keeps you out of a group; hazing is having to prove yourself to be a part of this group,” said Dennis Goodwin, a co-founder of Anti-Hazing Collaborative , an organization devoted to preventing hazing among young people.

While many fraternity members call one another “brothers,” Mr. Goodwin said he didn’t think students should be part of “families” that force them to “do something that could lead to death.”

Some anti-hazing activists said they were hopeful that prosecutions in cases such as Mr. Oakes’s would prove that these crimes were now taken seriously.

Rae Ann Gruver, the founder and president of the Max Gruver Foundation, has spent years trying to end hazing on college campuses. Her son, Max, died in 2017 “as a direct result of fraternity hazing,” the organization says online.

“The more and more these kids get prosecuted and indicted and actually see punishment, and that prosecutors are ready to prosecute them, that’s really going to deter these kids,” Ms. Gruver said.

Many states’ hazing laws are classified as misdemeanors, she said, which means less time in prison if convicted. If those laws change into felonies, no young adult “is going to want that on their record,” Ms. Gruver said.

In Virginia , where Mr. Oakes’s case is taking place, hazing is a misdemeanor.

“I do think fraternity headquarters are getting more on board and really having a no-tolerance policy and getting down to it, but it’s taking time,” Ms. Gruver said.

If someone hazes, she said, “it is against the law, and you should be prosecuted just like any other crime.”

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Putatively lethal ingestion of isopropyl alcohol-related case: interpretation of post mortem isopropyl alcohol and acetone concentrations remains challenging

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• Published: 22 October 2020
• Volume 135 , pages 175–182, ( 2021 )

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• Carine Dumollard 1 ,
• Jean-François Wiart 1 ,
• Florian Hakim 1 , 2 ,
• Christophe Demarly 3 ,
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Isopropyl alcohol, or propan-2-ol (IPA), is found in numerous chemicals including alcohol-based hand rubs whose use has been recently widely extended to the general population since the onset of the COVID-19 pandemic. This widespread of IPA use could potentially, but not necessarily, be responsible for an increase in IPA poisoning cases (e.g., in alcoholics and/or for suicide attempt, even more in a lockdown situation). Forensic identification of IPA-related fatalities remains challenging as IPA post mortem detection can also result from antemortem or post mortem production, or post mortem contamination. In order to illustrate this issue, we report the case of a 33-year-old man found dead with a bottle of pure IPA liquid close to him. Toxicological positive results only consisted in IPA (464, 260, 465 and 991 mg/L) and acetone (1560, 2340, 3040 and 1360 mg/L) in blood, vitreous humour, urine and bile, respectively (determinations using headspace gas chromatography with flame ionization detection). These IPA absolute concentrations and IPA-to-acetone ratios appear inferior to those usually reported in the literature (higher than 1000 mg/L and 1.1, respectively) in IPA poisoning cases. In conclusion, this death can be cautiously regarded as an IPA ingestion-related fatality in the hypothesis of a survival time which have promoted IPA metabolism to acetone: this hypothesis is supported by the putative limited IPA-ingested dose. This report emphasizes the fact that post mortem IPA and acetone concentration interpretation involves to take account of (i) results in multiple biological specimens, (ii) complete case history, and (iii) a search of possible IPA presence at the scene of death.

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Introduction

Isopropyl alcohol, propan-2-ol, or isopropanol (IPA) is a flammable and colourless liquid with a fruity odour and a slightly bitter taste. Cheap and easy to obtain, IPA is found in numerous industrial and household chemicals. As a result, IPA can be present in hand sanitizers or alcohol-based hand rubs (ABHRs that typically contain combination of alcohols: IPA, ethanol and/or n-propanol), and also in home cleaning products, disinfectants, antifreezes, cosmetics, solvents and skin lotions… [ 1 ]. It is noteworthy that since the onset of the influenza A (H1N1) pdm09 virus epidemic, ABHR use has recently been extended worldwide from healthcare staff to the general population. This ABHR widespread use opens up the possibility of an increase of IPA poisoning cases (e.g. in alcoholics and/or for suicide attempt, even more in a containment situation) as ABHRs are usually available in bottles that facilitate the ingestion of large amounts of liquids [ 2 , 3 ].

Several IPA intoxication case reports can be found in the literature (including some ABHR ingestion-related cases observed during an H1N1 pandemic) and treatment consists essentially on supportive therapy [ 2 , 3 , 4 , 5 , 6 , 7 ]. IPA intoxications can be fatal, but only few fatalities have been previously reported [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. In these published fatalities, observed IPA and acetone (its main metabolite) post mortem blood concentrations ranged from 200 to 37,000 mg/L and from 320 to 3000, respectively, and blood IPA-to-acetone ratio ranged from 0.33 to 25.

In practice, the interpretation of post mortem toxicological findings in order to diagnose IPA poisoning is tricky in forensic situations. Indeed, IPA post mortem detection in itself cannot be regarded as an evidence of antemortem IPA ingestion by the victim. The main hurdle is that quantifiable concentrations of IPA in post mortem biological fluids can have various origins: endogenous origin (i.e. acetone metabolism), post mortem contamination or production [ 11 , 12 , 15 ]. In this context, we report a fatality putatively related to an IPA poisoning in order to illustrate these interpretation pitfalls.

Case history

A 33-year-old man was found dead in his closed home. The victim had a past history of drug addiction, psychosis and an attempt of hanging himself. Several items were found close to the corpse: a knife, a cord, a letter and an unlabeled plastic bottle (1.5 L capacity) containing about 1.1 L of a colourless liquid. Autopsy took place 5 days after the death: this long delay can be explained by the fact that the death occurred just before a weekend, then the corpse (maintained at + 4 °C) had to be transported to the Institute of Legal Medicine, around 200 km from the place of death, and the autopsy was finally achieved on the following Tuesday. Autopsy revealed a beginning state of putrefaction, a pulmonary edema and multivisceral congestion (lungs, liver and kidneys). Neither natural diseases nor traumatic lesions were found. Autopsy examination attributed the fatality to a significant asphyxia syndrome possibly from a toxic origin in the context of a suicide attempt. Femoral (peripheral) blood could not be collected in this victim due to coagulation process and putrefaction phenomena, due to the relatively long delay between death and autopsy (5 days). Biological samples (cardiac blood collected in 2% sodium fluoride tube, vitreous humour, urine, bile and gastric content) were sent to the laboratory in glass-sealed tubes for toxicological analyses, together with the unknown liquid contained in the bottle.

Material and methods

Toxicological investigations consisted in comprehensive screenings of drugs and toxic compounds and were carried out in each biological sample and the unknown liquid using two published methods that are routinely used in forensic contexts in our laboratory [ 16 , 17 , 18 , 19 ]: (1) a liquid chromatography with high-resolution mass spectrometry detection method (LC-HRMS) using a homemade spectral library of more than 1650 substances and (2) a liquid chromatography with tandem mass spectrometry detection method (LC-MS/MS) for several classes of therapeutic drugs, drugs of abuse (DOA) and other toxicants.

More selective assays for several classes of therapeutic drugs, DOA and other toxicants were also performed using various methods: immunoassays, headspace gas chromatography with flame ionization detection (HS-GC-FID) and LC-MS/MS. In particular, a NF EN ISO 15189-accredited (scope no 8-3030 available on website www.cofrac.fr ) HS-GC-FID method was used for alcohols and acetone identification and quantification. Briefly, 200 μL of biological samples and 200 μL of internal standard (150 μL of acetonitrile in 100 mL of water) were introduced in a 22-mL HS vial, which was rapidly sealed with a silicone septum and aluminium cap. Separation was done in a 624CB column (1.8 μm; 30 m × 0.32 mm i.d.; Varian, Courtaboeuf, France) and detection was performed using a GC2010 Plus (Shimadzu, Marne-la-Vallée, France). For both IPA and acetone, the limit of detection (LOD) and the lower limit of quantification (LLOQ) in whole blood are estimated at 10 and 50 mg/L, respectively; standard curves are linear from 50 to 5000 mg/L, and interday CV and bias were less than 15%.

Neither drugs nor DOA were detected in biological samples and the unknown liquid. In particular, ethanol was negative and urinary ethyl glucuronide (a specific metabolite of ethanol) concentration was less than 0.1 mg/L. Positive results only consisted in IPA and acetone detection at high concentrations in all biological samples (Table 1 ). IPA was also found in the unknown liquid at a concentration of 785 g/L (i.e. > 99% if expressed as a volume percent).

After ingestion, IPA is rapidly absorbed and metabolized by alcohol dehydrogenases to acetone resulting in ketosis and ketonuria [ 20 , 21 ]. Mechanism of isopropanol toxicity is not fully elucidated but both IPA (mainly) and acetone contribute to central nervous system (CNS) depression [ 7 ]. The major toxic contribution of IPA itself is supported by several case reports that have shown clinical improvement while acetone blood concentrations were still rising [ 22 , 23 , 24 , 25 ]. IPA blood elimination half-life varies from 2.5 to 8 h and a small part is directly eliminated unchanged in urine and breath [ 1 , 5 ]. Acetone (blood elimination half-life averages about 22 h) is also partially eliminated unchanged in urine and breath. Data supporting formation of formate (and acetate) from acetone remain scarce, and this formation may be negligible. Indeed, elevation of osmolar gap can be observed in cases of IPA intoxication but metabolic acidosis has never been reported [ 7 ]. Moreover, acetone can be reduced to isopropanol, which is considered as a physiological minor pathway that can be enhanced in some pathological conditions such as diabetic ketoacidosis [ 12 , 15 , 26 ]. Owing to IPA fast absorption, clinical signs of poisoning occur rapidly, starting with digestive troubles (nausea, abdominal pain, vomiting, hematemesis) and further complicating by hypotension, CNS depression (headaches, dizziness, confusion) and coma [ 1 , 4 ].

The lethal dose of pure IPR is estimated to be around 200–400 mL [ 8 , 9 ]. In such case of IPA intoxication-related death, no specific organic lesions are found at autopsy. Common findings include pulmonary congestion and moderate to extensive bilateral pulmonary haemorrhage [ 8 , 9 ]. This is coherent with autopsy findings (i.e. pulmonary edema and multivisceral congestion) in our present case.

In our opinion, in case of IPA positive post mortem results, interpretation should be considered from two points of view: analytical findings in cases of documented IPA poisoning and analytical findings (including IPA presence) in circumstances that are not related to antemortem IPA poisoning. Nevertheless, these two points of view need clarification considering the very few studies available in the literature and their provided data that are barely comparable (Table 2 ).

IPA and acetone findings in post mortem cases related to documented IPA poisoning

Concerning toxicological findings, in 1962, Adelson had already reported IPA blood concentrations ranging from 200 to 2000 mg/L in five fatalities, together with acetonuria as a constant laboratory finding [ 8 ]. Nowadays, acetone presence (> 100 mg/L) is considered as a blood marker in cases of IPA poisoning (with the understanding that acetone presence is not specific of IPA poisoning) [ 9 , 26 ]. In a retrospective study, Alexander et al. reported 57 cases in which toxicological investigations revealed IPA presence with post mortem blood concentrations ranging from 100 to 4700 mg/L (mean: 2400 mg/L) together with acetone blood concentrations ranging from < 100 to 3200 mg/L (mean: 1240 mg/L) [ 9 ]. In fact, only 31 out of these 57 cases could be substantiated as resulting from IPA poisoning alone. In these 31 cases, IPA blood concentrations ranged from 100 to 2500 mg/L (mean: 1400 mg/L) and acetone blood concentrations ranged from 400 to 3000 mg/L (mean: 1700 mg/L). Accordingly, IPA and acetone blood concentrations did not appear to be effective tools to distinguish IPA poisoning to other causes of death.

In 2010, Molina reported eight cases of fatal IPA intoxications with high IPA blood concentrations ranging from 1480 to 37,000 mg/L (median: 1750 mg/L) and acetone blood concentrations ranging from 400 to 2000 mg/L (median: 1500) [ 12 ]. The average IPA-to-acetone ratio was 5.5 (range 0.8–25) in blood samples and 5.6 (range 1.0–18.6) in vitreous humour samples. In seven out of the eight cases, IPA blood concentration was greater than that of acetone, and IPA blood and vitreous humour concentrations were above 1000 mg/L. In six other IPA poisoning cases, Petersen et al. also reported high post mortem IPA blood concentrations (ranging from 500 to 6500 mg/L) together with high IPA-to-acetone ratios (mean: 3.70) [ 14 ].

These latter reports are not consistent with our present case where IPA concentration and IPA-to-acetone ratios are 464 mg/L and 0.29 in blood and 260 mg/L and 0.11 in vitreous humour, respectively. Nevertheless, as suggested by Jenkins et al. and Gaulier et al., low IPA concentration could be observed in post mortem blood from IPA-intoxicated victims who have survived long enough for IPA to be metabolized to acetone [ 11 , 13 ]. Indeed, this survival time between ingestion and death should be considered for interpretation. The blood kinetics of IPA and acetone had been studied in six non-fatal cases after IPA ingestion [ 20 ]: IPA-to-acetone ratio decreases from the fifth hour after ingestion. Unfortunately, this major issue about survival time was unavailable in published post mortem reports. Merricks et al. also reported a case of IPA poisoning with cardiac blood concentrations for IPA (370 mg/L) and acetone (320 mg/L) that were in the low range of (or lower than) values reported by Alexander and Molina. The same authors reported another fatality for which IPA bottles were found at the scene. In this case, IPA/acetone post mortem concentrations were close to those observed in our present case: 880/1960 mg/L in femoral blood, 640/1960 mg/L in cardiac blood, 760/2990 mg/L in urine and 550/2510 mg/L in vitreous humour [ 11 ]. Lastly, in another fatality related to both hypothermia and IPA intoxication (bottle of rubbing alcohol present at the scene), IPA/acetone post mortem concentrations were also close to those of the presented case: 860/1160 mg/L in femoral blood and 1040/1300 mg/L in vitreous humour [ 10 ].

Furthermore, some other reports of specific intoxication cases where IPA was an ingredient of an ingested mixture should be noted (PineSoil™), but finally not considered as the main toxicant related to the cause of death. In two fatalities, 1-alpha-terpineol, the major terpene alcohol of pine oil, was reported to be the main toxicant [ 27 , 28 ].

To summarize, in post mortem cases related to documented IPA intoxication, acetone is also and always detected in biological fluids, IPA blood concentrations seem regularly high and exceeding 1000 mg/L and IPA-to-acetone ratios are usually over 1.1 in blood and vitreous humour (this latter specimen even appears to be the most appropriate matrix as it demonstrates a weaker ratio variability than blood). However, an IPA poisoning hypothesis should not be discounted when a low IPA post mortem concentration (< 1000 mg/L) and/or IPA-to-acetone ratio < 1.1 are observed, in particular if the case history suggests a significant survival time and/or reports a potential source of exposure to IPA (as in the present case with the presence of a bottle of pure IPA close to the corpse) [ 11 ].

IPA and acetone findings in post mortem cases not related to IPA poisoning

Due to various circumstances such as IPA antemortem or post mortem production as well as post mortem contamination, the detection of IPA in post mortem samples is thus not a formal evidence of IPA antemortem exposure [ 12 ]. As aforementioned, 26 out of the 57 cases reported by Alexander et al. were not related to IPA intoxication: in these cases, post mortem blood IPA (range: 100 to 4700 mg/L) and acetone (range: < 100 to 3200 mg/L) concentrations were not significantly different from those observed in the 31 cases of documented IPA poisoning [ 9 ]. In a larger series comprising 162 cases not related to IPA intoxication, Jenkins et al. reported post mortem concentrations ranging from 20 to 390 mg/L (IPA) and from 20 to 830 mg/L (acetone) in femoral blood, from 20 to 350 mg/L (IPA) and from 20 to 870 mg/L (acetone) in cardiac blood, from 20 to 380 mg/L (IPA) and from 50 to 1100 mg/L (acetone) in vitreous humour, and from 20 to 380 mg/L (IPA) and from 50 to 1300 mg/L (acetone) in urine. In this study, observed IPA concentrations and IPA-to acetone ratios (mean: 0.42 in cardiac blood, 0.24 in femoral blood, 0.15 in vitreous humour and 0.20 in urine) are definitely lower than in cases of documented IPA poisoning and it is concluded that the presence of IPA is the consequence of acetone metabolism (embalmed and decomposed cases were excluded from the study) [ 11 ].

There are several situations leading to IPA antemortem production from acetone. The main one is diabetic ketoacidosis where insulin deficiency and glucagon excess lead to hyperglycaemia, production of ketone bodies including acetone and acidosis [ 14 , 29 ]. Davis et al. were the first to confirm and demonstrate IPA production from acetone reduction [ 15 ]. Furthermore, these authors reported IPA and acetone post mortem blood concentrations ranging from 10 to 290 mg/L and from 60 to 620 mg/L, respectively, in eight decedents with history of diabetes mellitus, gastrointestinal disorders or sepsis, but without antemortem exposure to IPA. Molina reported 39 cases of diabetes mellitus with post mortem concentrations up to 500 mg/L (IPA) and 1950 mg/L (acetone) in blood and up to 500 mg/L (IPA) and to 1120 mg/L (acetone) in vitreous humour. The corresponding IPA-to-acetone ratios averaged 0.39 (range: 0.04 to 1.0) in blood and 0.08 (range: 0.02 to 1.1) in vitreous humour [ 12 ]. Petersen et al. reported 134 cases with diabetic ketoacidosis where post mortem IPA blood concentrations (mean: 151 mg/L; range: 30 to 1000 mg/L) and IPA-to-acetone ratios (mean: 0.29) were significantly ( p  < 0.005) lower than those observed in six IPA poisoning cases [ 14 ].

Associated with excessive ethanol ingestion and poor nutritional intake, alcoholic ketoacidosis constitutes another source of antemortem IPA production consecutive to acetone production from fatty acid and ethanol metabolisms [ 30 , 31 ]. In 29 chronic ethanol users, Molina reported post mortem concentrations up to 710 mg/L (IPA) and 1950 mg/L (acetone) with IPA-to-acetone ratios averaging 1.1 in blood and up to 810 mg/L (IPA) and 2310 mg/L (acetone) with IPA-to-acetone ratios averaging 0.77 in vitreous humour [ 12 ]. Petersen et al. reported 41 cases (scene evidence of ethanol abuse and post mortem proof of alcoholic liver disease) with post mortem IPA blood concentrations (mean: 185 mg/L; range: 100 to 460 mg/L) and IPA-to-acetone ratios (mean: 0.52) significantly ( p  < 0.005) lower than those observed in six IPA poisoning cases [ 14 ]. Overall, these IPA and acetone post mortem concentrations in alcoholic ketoacidosis-related decedents are similar to those observed in cases of diabetes mellitus, although somewhat higher IPA-to-acetone ratios were observed. Nevertheless, in this context of chronic ethanol use, the presence of high concentrations of ethanol in blood and vitreous humour (82% of the 29 cases reported by Molina [ 12 ]) samples would help to determine the origin of IPA.

IPA antemortem production from acetone can occur in other physiopathological conditions, such as infections, dehydration, malnutrition or hypothermia. Post mortem IPA concentrations in blood or vitreous humour of dehydrated and/or malnourished decedents appear to be relatively low (below 220 mg/L). Conversely, in infection cases ( n  = 11), Molina reported post mortem IPA concentrations that were relatively high in blood (median: 700 mg/L; up to 9100 mg/L), but low in vitreous humour (median 100 mg/L; up to 300 mg/L). It is of note that acetone presence (in only 18% of the cases) was inconstant in these infection-related cases [ 12 ]. In hypothermia cases, post mortem IPA concentrations remain very low (below 20 mg/L) in blood and vitreous humour [ 32 ].

Depending on the microorganisms and the substrates that are present, putrefaction phenomenon in decomposed bodies commonly leads to the production of ethanol and other alcohols, comprising IPA and acetone, by bacteria (mostly Escherichia coli , Clostridium perfringens , Enterococcus faecalis and Clostridium sporogenes ) or yeasts (mostly Candida albicans and Saccharomyces cerevisiae ) [ 33 , 34 ]. In decomposing bodies, IPA and acetone concentrations seem to be < 1000 mg/L and < 500 mg/L in blood and vitreous humour, respectively, whereas IPA-to acetone ratios are more variable. Whatever, low ethanol concentrations and decomposed state of the body are good indicators of probable post mortem IPA production [ 12 , 35 ].

Post mortem contamination by IPA can sometimes occur, mainly in cases of embalming (embalming fluids usually contain methanol, and often isopropanol, formaldehyde or ethanol), and “apparently” in some cases where the body was washed with IPA before post mortem tissue procurement as suggested by Molina [ 12 ]. Nevertheless, this post mortem contamination is questionable as penetration of IPA through the intact skin seems hardly observed [ 36 ]. Even if IPA post mortem concentrations can be very high in some of these particular cases, the regular absence (over the physiological range) of acetone together with the case history allows the identification of post mortem contamination [ 12 ].

Lastly, besides IPA poisoning cases, small amounts of IPA can be sometimes detected in post mortem samples as the consequence of antemortem IPA exposure in some specific situations: e.g. in workers exposed to IPA (inhalation may be a route of exposure which, however, is limited regarding safety at work) or deaths occurring after binge drinking of alcoholic beverages in which IPA is present as a congener of ethanol [ 37 ]. However, in such sudden deaths of alcoholics, even if determination of butanol-1 and other congeners is advisable, observed IPA post mortem blood concentrations due to this “congeneric” presence remain low (< 50 mg/L) [ 38 ].

To sum up, IPA (+/− acetone) can be detected in post mortem samples from cases not related to IPA poisoning. These situations can be divided in (i) cases where IPA is detected but not acetone (post mortem contamination cases including embalming cases, post mortem tissue procurement), (ii) cases where IPA (+/− acetone) concentration remains low, i.e. regularly < 200 mg/L (dehydration and/or malnutrition, hypothermia, IPA present as a congener of ethanol) and (iii) cases where IPA and acetone concentrations are sometimes comparable with those observed in IPA poisoning cases (diabetic ketoacidosis, alcoholic ketoacidosis, infections and putrefaction phenomenon). In this latter category, if decomposition can certainly be easily identified (e.g. because of ethanol presence and decomposed state of the body), other situations are not readily identifiable without documented medical history of the victim and/or additional investigations (e.g. microbiological ones in order to identify bacteria or yeasts involved in IPA post mortem production). In order to distinguish these cases from IPA poisoning ones, low concentrations (< 1000 mg/L) [ 12 ] of IPA both in blood and vitreous humour are frequently helpful, as well as IPA-to-acetone ratios that appear to be regularly, even if not systematically, below 1.0, especially in vitreous humour.

IPA and acetone findings in the reported case

Beyond autopsy findings (i.e. pulmonary edema and multivisceral congestion) that are not specific but consistent with those observed in cases of IPA poisoning, analytical findings in the reported case are eligible for consideration based on all aforementioned points.

On the one hand, IPA poisoning hypothesis is supported by IPA and acetone presence in all biological samples at not negligible concentrations (greater than 200 mg/L) and by the presence of a bottle of pure IPA close to the victim. Nevertheless, two key elements are not supportive of a lethal ingestion of isopropyl alcohol: (1) IPA concentrations (464 mg/L in cardiac blood and, more specifically, 260 mg/L in vitreous humour) remain clearly below the usually reported ones in IPA poisoning cases (> 1000 mg/L) and (2) observed IPA-to-acetone ratios (0.29 in cardiac blood and, more specifically, 0.11 in vitreous humour) are also far below expected ones (> 1.1). It is noteworthy that the long delay between death and autopsy (5 days) could have participated to the decrease of IPA and acetone concentrations and/or to acetone conversion to IPA by bacterial alcohol dehydrogenase [ 33 ], even if the corpse was maintained at + 4 °C. Nevertheless, there is no clear data in the literature supporting these hypotheses. Petersen et al. investigated the post mortem interval between death and autopsy, but only a weak correlation between this delay and an upper IPA-to-acetone ratio in diabetic ketoacidosis post mortem cases was observed [ 14 ].

On the other hand, even if two previously mentioned categories (cat1 and cat2) of situations not related to IPA poisoning can be here excluded owing the absence of ethanol and both IPA and acetone concentrations over 200 mg/L, another hypothesis (cat3) should be considered: diabetic ketoacidosis, alcoholic ketoacidosis, infections or decomposition. Because of the decomposed state of the body (slight putrefaction) and the absence of ethanol, the hypothesis of a putrefaction phenomenon (leading to a significant increase of IPA and acetone) can reasonably be ruled out. In the present case, IPA blood and vitreous humour concentrations together with IPA-to-acetone ratios are in the range of those observed in other situations (ketoacidosis and infections). There was no available medical information to support (or to exclude) possible diabetic ketoacidosis, alcoholic ketoacidosis or infection status in the victim.

All in all, this case can be cautiously considered as related to a lethal ingestion of IPA due to two points: (1) IPA pure liquid (originally of unknown origin) close to the victim and (2) hypothesis of a significant survival time which has promoted IPA metabolism to acetone. Indeed, the possibility of a prolonged agony should be considered considering the probably limited volume of pure IPA ingested by the victim of around 400 mL (1100 mL of IPA was still present in the plastic bottle of 1500-mL capacity).

The interpretation of post mortem isopropyl alcohol and acetone concentrations, as well as IPA-to-acetone ratios, remains challenging mainly due to overlapping values between documented IPA poisoning cases and other cases not related to IPA poisoning. When isopropanol is detected in post mortem samples, by taking into account analytical findings in multiple biological specimens (and their confrontation with literature data), complete case history and search of possible IPA presence at the scene of death may provide reasonable explanations of a possible cause of death. Finally, in the current situation of the COVID-19 epidemic where ABHRs are more easily accessible, it is noteworthy that in cases of death suspected to be in relation with ABHR ingestion, post mortem detection of other constituents of the liquid (i.e. ethanol and n-propanol) simultaneously with IPA and acetone can be helpful for diagnostic [ 3 ].

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Dumollard, C., Wiart, JF., Hakim, F. et al. Putatively lethal ingestion of isopropyl alcohol-related case: interpretation of post mortem isopropyl alcohol and acetone concentrations remains challenging. Int J Legal Med 135 , 175–182 (2021). https://doi.org/10.1007/s00414-020-02444-4

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Received : 11 May 2020

Accepted : 14 October 2020

Published : 22 October 2020

Issue Date : January 2021

DOI : https://doi.org/10.1007/s00414-020-02444-4

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Case Study: Methanol Poisoning from Adulterated Liquor

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Traditionally, food safety issues associated with alcoholic beverages focus on chemical or physical hazards from the processing line. Intoxication with alcoholic beverages, as it relates to food safety, is less reported in the literature. However, there occasionally arise incidents where the adulteration of an alcoholic product leads to severe illness or death upon consumption or intoxication. The addition of cheap methanol to illicitly produced liquor—a rising issue in Asia—is increasingly being studied as a food safety and food adulteration issue.

In this case study, seven people were hospitalized with alcohol poisoning from October to November 2020. Two victims suffered from methanol poisoning, one person died, and four others suffered eye and brain damage. All of the cases stemmed from consumption of the same commercial liquor produced by a local company in Vietnam. 

One victim reported drinking liquor bought from a grocery store, along with three other people. The next day, the victim suffered from headache, blurred vision, and fatigue. He was taken to the Poison Control Center Hospital and hospitalized for alcohol poisoning; shortly thereafter, the victim entered a coma. The test result of the liquor in this victim's system showed a methanol content of 20.21 percent, with an additional ethanol level of 11.42 percent. The three others who drank the same liquor were hospitalized and diagnosed with methanol poisoning; fortunately, however, all of them recovered after treatment. 

One of the other three patients, a 22-year-old male, registered a very high level of blood-methanol after drinking the same liquor over three consecutive days. Although this patient had a toxic level of methanol in his system, hospital medical professionals were able to detoxify him. Another patient, a 32-year-old male, was diagnosed with industrial methanol poisoning at a lower level. The patient was hospitalized in a state of deep coma, with dilated pupils and low blood pressure. Test results showed a blood-methanol level of 141 mg/dL. He recovered gradually, due to the administration of timely treatment. 

Methanol Poisoning from Adulterated Liquor

In some countries where the official sale of alcoholic drinks is prohibited, people may buy alcohol that is produced under dubious conditions and sold on the black market. These products are sometimes adulterated. The most serious poisoning cases involve liquor containing industrial methanol instead of ethanol as a basic ingredient. Methanol negatively affects mental and physical health and may result in death. 

These cases, known as industrial methanol poisoning, happen due to the consumption of adulterated liquor that contains a high concentration of methanol. This type of product comes with its own name and label, registration, and source information, which makes it appear authentic. This enhances the danger, because consumers can be misled by the appearance of a regular commercial product.

Methanol, commonly known as industrial alcohol, is the simplest alcohol with the formula CH3OH. In distilled spirits, methanol is derived from the breakdown of macromolecules, such as hemicellulose, pectin, lignin, and xylan, during fermentation. Methanol itself is less toxic, although its metabolites are very toxic. When entering the body, methanol is metabolized by alcohol dehydrogenase—an enzyme that metabolizes alcohol in the liver, producing formaldehyde, which is 33 times more toxic than methanol and causes clinical symptoms. Formaldehyde is then rapidly converted to formic acid (which is six times more toxic than methanol) by formaldehyde dehydrogenase, which inhibits cytochrome oxidase in the optic nerve and disturbs axonal conduction. Finally, formic acid is converted to carbon dioxide and water. 

Methanol affects mainly the central nervous system with symptoms of intoxication, somnolence, stupor, convulsions, and/or coma. A concentration of methanol in excess of the permissible limit can lead to poisoning for users. The Vietnamese standard (TCVN 7043: 2013) stipulates that the methanol content in 1 liter of 100-percent-proof ethanol is not more than 2,000 mg.

Difference between Ethanol and Methanol

Ethanol is alcohol produced by the distillation of starches from grains, rice, etc. Ethanol is used as a main ingredient in alcoholic beverages, perfumes, and mouthwashes. At regulated levels, it is not harmful to the human body. Traditional methods for the distillation of liquor from grains do not cause poisoning. Products with a high methanol concentration, as in the above-mentioned cases, come from mixing traditional liquor with industrial alcohol and bottling it for sale as low-priced, adulterated liquor. 

Methanol is produced from materials containing cellulose and is used to dissolve inorganic or organic substances for non-drinking or antiseptic purposes. When it is misused as an ingredient in adulterated alcoholic beverages, it can be highly toxic and cause serious poisoning. The allowable methanol content in liquor is 0.1 percent, but the percentage of methanol in adulterated liquor is often much higher. 

Due to differences in anatomy and physical health, people will have different reactions when drinking liquor containing methanol. Some people experience normal alcohol intoxication and may not show any symptoms of poisoning until a day or two later. Methanol is metabolized and eliminated from the body very slowly, so if the patient is not affected immediately, methanol can be dangerous since it remains at a detectable level in the body up to eight days after ingestion. However, if methanol is allowed to exist in the body for many hours, then the toxin will gradually convert into formic acid, which can lead to eye and brain damage.

Risks of Methanol Poisoning

Those who are poisoned by methanol usually show signs of intoxication within 30 minutes of consumption or possibly later, depending on how much liquor they consume. Usually, methanol poisoning includes two stages:

• Insidious stage (within the first few hours to 30 hours): Symptoms are initially subtle, mildly inhibiting nerves, sedation, and apathy, so they often go ignored or undetected.
• Poisoning stage (can manifest within hours or up to two days after consumption): Symptoms include vomiting, abdominal pain, impaired vision and eye pain, headache, slow reaction time, limping, impaired senses of taste and smell, impaired memory, muscle stiffness, and lack of motor control or convulsions. Severe poisoning can lead to unconsciousness (coma), hypotension, heart failure, and death.

Trace amounts of methanol are present in natural fruit juices, which are a nontoxic source of methanol due to its low content. Methanol is also a nontoxic product of alcoholic fermentation. When ethanol and methanol are both added to alcoholic beverages, however, the toxic metabolism of methanol appears to be slower and manifests as contamination. At a late stage of intoxication, patients and physicians may notice the symptoms of ethanol poisoning and miss the indications of methanol poisoning. For all clinical cases of suspected general alcohol intoxication, simultaneous testing of both ethanol and methanol should be performed.

Avoiding Liquor Adulterated with Methanol

Adulterated liquor is a public health issue because it is produced without regulatory or market oversight, and the addition of high percentages of industrial methanol poses a serious public health threat to consumers. To avoid liquor adulterated with methanol, only liquor of origin with clear labels and stamps certified by authorities should be sold at a retail establishments and consumed by end users. No liquor with a methanol content greater than 0.1 percent should be sold or consumed. 

To detect the presence of high levels of methanol in adulterated liquor, researchers in 2020 reported the development of a palm-sized, sensor–smartphone system for the on-demand analysis of beverages. The sensor system was reported to quantify methanol concentrations in 89 pure and methanol-contaminated alcoholic beverages from six continents, performing accurate analyses for 107 consecutive days. 1 This device, and other technologies under development, could be used to assist distillers, regulatory authorities, public health workers, and even consumers in easily screening for methanol in alcoholic beverages.

• Abegg, Sebastian, Leandro Magro, Jan van den Broek, Sotiris E. Pratsinis, and Andreas T. Güntner. "A pocket-sized device enables detection of methanol adulteration in alcoholic beverages." Nature Food 1 (2020): 351–354. https://doi.org/10.1038/s43016-020-0095-9 .

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Dr. Bảo Thy Vương is Head of the Health Sciences Faculty at Mekong University in Vietnam. Her research interests include food safety, public health, and nutrition.

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Alcohol Poisoning

Alcohol poisoning occurs when a toxic amount of alcohol has been consumed, usually in a short period of time. A person with alcohol poisoning can appear extremely disoriented, unresponsive or unconscious, with shallow breathing. Alcohol poisoning can be fatal and should be taken very seriously. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) has done a lot of research about alcohol poisoning. To learn more about what happens to your body when you have alcohol poisoning, please review the  NIAA website .

Binge Drinking

Alcohol poisoning often occurs when someone drinks too much in a short period of time. This is also referred to as binge drinking. What is binge drinking? According to NIAAA, binge drinking is "a pattern of drinking alcohol that brings blood alcohol concentration (BAC) to 0.08 gram percent or above." For a typical male adult, this equates to consuming five or more drinks. For a typical female adult, it would be consuming four or more drinks in about a two-hour period.

Blood Alcohol Concentration Charts

There are many factors that affect your Blood Alcohol Concentration (BAC) when you drink. Some of these include:

• a person's size, gender and physical condition
• how much they have eaten prior to drinking
• how much sleep they have had
• what medications they are taking
• the actual alcohol content of their chosen "drink."

For more information, please reference the BAC charts for  men and women.